EA037871B1 - AZABENZIMIDAZOLE DERIVATIVES AS pI3K BETA INHIBITORS - Google Patents

Abstract

The invention relates to azabenzimidazole derivatives of Formula (I)wherein the variables have the meanings defined in the claims. The compounds according to the invention are useful as pI3K inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

Description

The technical field to which the invention relates

The present invention relates to azabenzimidazole derivatives useful as β3Κβ inhibitors. In addition, the present invention relates to pharmaceutical compositions containing said compounds as an active ingredient, as well as to the use of said compounds as a medicament.

Background of the invention

There are three classes of phosphoinositide 3-kinases (PI3K): class I, class II, and class III. Class I PI3Ks are most associated with human cancer [K.D Courtney, R.B. Corcoran and J.A. Engelman (2010) Journal of Clinical Oncology, 28; 1075]. Phosphoinositide 3-kinases (PI3K) of class I are divided into two subclasses: class IA - consisting of the catalytic subunit p110 (p110a, p110b or p110d) and the regulatory subunit p85 (p85a, p55a and p50a, p85b or p55g), and class IB - PI3K, characterized by the p110g catalytic subunit and the p101 and p84 regulatory subunits [B. Vanhaesebroeck and M.D. Waterfield (1999) Experimental Cell Research 253, 239-254]. PI3K class IA are activated in a number of solid and non-solid tumors by mutation or deletion of the tumor suppressor PTEN (homologue of phosphatase and tensin) or, in the case of p110a, by activating mutations [K.D Courtney, R.B. Corcoran and J.A. Engelman (2010) Journal of Clinical Oncology, 28; 1075]. PI3K can also be activated by tyrosine kinase receptor (RTK); p110b can be activated by G-protein coupled receptors [K.D Courtney, R.B. Corcoran and J.A. Engelman (2010) Journal of Clinical Oncology, 28; 1075]. Immediately after activation, phosphoinositide-3-kinases catalyze phosphorylation of phosphatidyl-4,5-diphosphate, which leads to the formation of phosphatidyl-3,4,5-triphosphate (PIP3) [Zhao L., Vogt P.K. (2008) Oncogene, 27, 5486-5496]. PTEN counteracts PI3K activity by dephosphorylation of PIP3 [Myers M.P., Pass I., Batty I.H., Van der Kaay J., Stolarov J.P., Hemmings B.A., Wigler M.H., Downes C.P., Tonks N.K. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 13513-13518]. PIP3, formed as a result of PI3K activation or preserved as a result of PTEN inactivation, binds to a subset of lipid-binding domains in downstream targets, such as the plextrin-homologous domain of the Akt oncogene, thereby recruiting it into the plasma membrane [Stokoe D., Stephens LR, Copeland T., Gaffney PR, Reese S. V., Painter GF, Holmes A. B., McCormick F., Hawkins PT (1997) Science 277, 567-570]. Once attached to the plasma membrane, Akt phosphorylates several effector molecules that are involved in a variety of biologically important processes such as metabolism, differentiation, proliferation, longevity and apoptosis [D.R. Calnan and A. Brunet (2008), Oncogene, 27; 2276)].

Several studies point to the key role of p110b in PTEN-deficient tumors. For example, gene knockout p110b, but not p110a makes it possible to block tumor formation and Akt activation caused by loss of Pten in the anterior prostate gland in a mouse model [Jia S., Liu Z., Zhang S., Liu P., Zhang L., Lee SH, Zhang J., Signoretti S., Loda M., Roberts TM, Zhao JJ Nature, 2008; 454: 776-9]. In addition, other studies have shown that a subset of human PTEN-deficient tumor cell lines is susceptible to inactivation of p110b rather than p110a [Wee S., Wiederschain D., Maira SM, Loo A., Miller C., deBeaumont R., Stegmeier F., Yao YM, Lengauer C. (2008), Proc. Natl. Acad. Sci (USA); 105, 13057]. PTEN deficiency, either as a result of genetic inactivation or decreased expression, is often observed in human-specific cancers such as GBM, endometrial, lung, breast cancers and, among others, prostate cancer [K.D Courtney, R.B. Corcoran and J.A. Engelman (2010) Journal of Clinical Oncology, 28; 1075].

These studies suggest that treatment of PTEN-deficient cancers with agents that inhibit p110b may be therapeutically beneficial.

In addition to its role in cancer, p110b may be a target for anticoagulant therapy. In mouse models, it was confirmed that inhibition of PI3Kb can prevent the formation of stable adhesive contacts with integrin a _IIb b ₃ , which eliminates the formation of an occlusive thrombus without prolonging bleeding time [SP Jackson et al. (2005) Nature Medicine 11, 507-514].

Moreover, the phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) / AKT signaling pathway is often activated during the progression of prostate cancer (PCa) through the loss or mutation of the phosphatase and tensin homologue (PTEN) gene. It is the second major inducer of MSa development after the androgen receptor (AR) signaling pathway. Combination with hormonal therapy improved the efficacy of PI3K / AKT agents in PTEN-negative MSa models. Upregulation of AR targeting genes upon PI3K / AKT inhibition suggests compensatory interactions between PI3K-AR pathways, which may require co-targeting of the AR pathway for optimal treatment efficacy [Marques RB, et al., High Efficacy of Combination Therapy Using PI3K / AKT Inhibitors with Androgen Deprivation in Prostate Cancer Preclinical Models. Eur. Urol. (2014), http://dx.doi.Org/10.1016/j.eururo.2014.08.053]. Thus, PI3Ke inhibitors can be advantageously combined with antiandrogenic therapeutic agents, including androgen receptor antagonists and androgen biosynthesis inhibitors, in PTEN-negative prostate cancer.

WO 2012/116237 discloses heterocyclic compounds that modulate the activity

PI3 kinases.

WO 2011/123751 describes heterocyclic compounds as selective inhibitors of PI3 K activity.

WO 2011/022439 discloses heterocyclic compounds that modulate PI3 kinase activity.

WO 2008/014219 describes thiozolidinedione derivatives as PI3 kinase inhibitors.

WO 2013/028263 relates to pyrazole pyrimidine derivatives as PI3 kinase inhibitors.

WO 2012/047538 relates to benzimidazole derivatives as PI3 kinase inhibitors.

WO 2013/095761 relates to imidazopyridine derivatives as PI3 kinase inhibitors.

US 2013/0157977 relates to benzimidazole boronic acid derivatives as PI3 kinase inhibitors.

WO 2009/021083 describes quinoxaline derivatives as PI3 kinase inhibitors.

WO 2007/103756 describes the preparation of thiazolones for use as PI3 kinase inhibitors.

WO 2011/041399 describes benzimidazolyl (morpholinyl) purines and related compounds as PI3Kδ inhibitors and their preparation and use for the treatment of PI3K-mediated diseases.

WO 2009/088990 describes the preparation of pyrazolopyrimidines and other heterocyclic compounds as therapeutic modulators of PI3 kinase.

Therefore, there is an urgent need for new inhibitors of PI3Ke kinase, opening up new avenues for the treatment or prevention of cancer, specifically PTEN-deficient cancers, more specifically prostate cancer. Therefore, it is an object of the present invention to provide such compounds.

Brief description of the invention

The compounds of the present invention have been found to be useful as PI3Ke inhibitors. The compounds according to the present invention and compositions based on them may be useful for the treatment or prevention, in particular for the treatment of diseases such as cancer, autoimmune disorders, cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, allergies, pancreatitis, asthma, multiple organ failure, kidney disease, platelet aggregation, impaired sperm motility, transplant rejection, tissue rejection, lung damage, etc.

The present invention relates to compounds of formula (I)

their tautomers and stereoisomeric forms, where

R ³ is C1-4 alkyl; -CH (OH) -CH2-R ^q ; C1-4αalkyl substituted at the same atom R ¹ is hydrogen, —C (= O) OH, —C (= O) NH ₂ , —NH ₂ , R ² is

- 2 037871 IU of carbon with one -OH and one Het ¹ ; selected from the group consisting of fluoro, -NH- (C = O) -C _1-4 alkyl, -NH- (SO ₂ ) -C _1-4 α-alkyl, or C _1-4 alkyl substituted with one substituent, -OH , -NH ₂ , -O- (C = O) -C _1-4 alkyl, - (C = O) -OC _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , -NH-C _1-4 alkyl-SO ₂ -CH ₃ ,

-N (CH3) -C1-4alkyl-OH, - (C = O) -NH-C1-4alkyl-OH, -O- (C = O) -CH (NH2) -C1-4alkyl,

-O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar, ^ο , -NH-C1-4 ^{alkyl-OH, Het 1} , -O-C (= O) -C1-4 alkyl- Het ¹ ,

-C (= O) -Het ¹ and -NH-C (= O) -Het ¹ ;

R ^q is Het ¹ , fluoro, -OH, -NH ₂ , -O- (C = O) -C _1-4 alkyl, -NH- (C = O) -C _1-4 alkyl,

-NH- (SO ₂ ) -C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , -NH-C _1-4 alkyl-SO ₂ -CH ₃ , -N (CH ₃ ) -C _1-4 alkyl-OH,

-O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl, -O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar,

or —NH — C _1-4 alkyl — OH;

Ar is phenyl optionally substituted with one hydroxy;

R ^4a is hydrogen, C1-4 alkyl, Het ^a, or C1-4 alkyl substituted with one or more substituents each independently selected from the group consisting of —OH, —NR5R ⁶ and Het ^a ;

R ^4b is hydrogen, halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents; or

R ^4a and R ^4b are taken together to form, together with the phenyl ring to which they are attached, the structures of formula (a-1), (a-2), (a-3), (a-4) or (a-5 ):

X is —NH—, —O—, —N (C _1-3 alkyl) - or —N (hydroxy — C _1-3 alkyl) -;

both R ⁷ are the same and are selected from the group consisting of hydrogen, fluoro and methyl; or both R ⁷ substituents are taken together to form, together with the common carbon atom to which they are attached, cyclopropyl, cyclobutyl or oxetanyl;

both R ⁸ are the same and are selected from the group consisting of hydrogen and methyl; or both R ⁸ are taken together to form, together with the common carbon atom to which they are attached, cyclopropyl, cyclobutyl or oxetanyl;

R ⁵ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with one —OH;

R ⁶ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with one —OH;

wherein Het ¹ is a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) _p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, —NH ₂ , C _1-4 alkyl, —S (= O) ₂ —C _1-6 alkyl, —C _1-4 alkyl-S (= O) ₂ —C _1-6 alkyl, hydroxyl, C _1-4 alkyloxy, fluoro, cyano and C _1-4 alkyl substituted with one hydroxy; or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring A;

wherein Ring A is cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5-, or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) _p and N; wherein said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl are optionally substituted with one or two C _1-4 alkyl substituents, one C _1-4 alkyl substituent and one substituent, representing hydroxy, or one substituent representing hydroxy;

each Het ^a independently represents a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) _p and

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N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C _1-4 alkyl, —S (= O) ₂ —C _1-6 alkyl , hydroxy, —C _1-4 alkyl-S (= O) ₂ —C _1-6 alkyl and C _1-4 alkyl substituted with one hydroxy; or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring B;

wherein ring B is cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) p and N; wherein said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl are optionally substituted with one or two C _1-4 alkyl substituents, one C _1-4 alkyl substituent and one substituent, representing hydroxy, or one substituent representing hydroxy;

p is 1 or 2;

and their N-oxides, pharmaceutically acceptable addition salts and solvates.

The present invention also relates to methods for preparing the compounds of the present invention and pharmaceutical compositions containing them.

It has been found that the compounds of the present invention inhibit PI3Ke by themselves or can be metabolized to a (more) active form in vivo (prodrugs) and thus can be useful in the treatment or prevention, in particular in the treatment of diseases such as cancer, autoimmune disorders, cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, allergies, pancreatitis, asthma, multiple organ failure, kidney disease, platelet aggregation, impaired sperm motility, transplant rejection, tissue rejection, lung damage, etc.

From the aforementioned pharmacology of the compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, it follows that they may be suitable for use as a medicament.

In particular, the compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates may be useful in the treatment or prevention, in particular in the treatment, of cancer.

The present invention also relates to the use of compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for the preparation of a medicament for inhibiting PI3Ke, for the treatment or prevention of cancer.

The present invention will be described below. Various aspects of the present invention are defined in more detail in the following sections. Each aspect defined in this way may be combined with any other aspect or aspects unless explicitly stated otherwise. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Detailed description

When describing the compounds of the present invention, the terms used are to be construed in accordance with the following definitions, unless the context indicates otherwise.

If any variable occurs more than once in any component or any formula (for example, in formula (I)), then its definition in each case is independent of its definition in each other case.

It is assumed that the term substituted in all cases of use in the present invention means, unless otherwise indicated or clearly follows from the context, that one or more hydrogen atoms, in particular from 1 to 3 hydrogen atoms, preferably 1 or 2 hydrogen atoms, more preferably 1 hydrogen atom, at the atom or radical designated using the expression substituted, are replaced with a selected from the indicated group, provided that the normal valence is not exceeded and that a chemically stable compound is formed as a result of the substitution, i.e. a compound that is stable enough to withstand isolation from the reaction mixture to a suitable degree of purity and formulation into a therapeutic agent.

If there are two or more substituents on a fragment, then, unless otherwise indicated or clearly follows from the context, they can replace hydrogen atoms at the same atom, or they can replace hydrogen atoms at different atoms in the fragment.

The person skilled in the art will understand that, unless otherwise indicated or clearly indicated by the context, a substituent on a heterocyclyl group may substitute for any hydrogen atom on a ring carbon atom or on a ring heteroatom.

The prefix C _x-y (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, the C _1-6 alkyl group contains from 1

- 4037871 to 6 carbon atoms, a C _1-4 alkyl group contains from 1 to 4 carbon atoms, a C _1-3 alkyl group contains from 1 to 3 carbon atoms, a C _3-6 cycloalkyl group contains from 3 to 6 carbon atoms, and

etc.

The term halogen as a group or part of a group is a generic name for fluorine, chlorine, bromine, iodine, unless otherwise indicated or clearly follows from the context.

The term C _1-6 alkyl as a group or part of a group refers to a hydrocarbyl radical of the formula CnH _{2n + 1} , where n is a number in the range from 1 to 6. C _1-6 alkyl groups contain from 1 to 6 carbon atoms, preferably from 1 up to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, even more preferably from 1 to 2 carbon atoms. Alkyl groups can be linear or branched and may be substituted as indicated herein. When a subscript is used in this document after a carbon atom, the subscript means the number of carbon atoms that a named group may contain. Thus, for example, C _1-6 alkyl includes all linear or branched alkyl groups with 1-6 carbon atoms and therefore includes, for example, methyl, ethyl, n-propyl, isopropyl, 2-methylethyl, butyl and its isomers (e.g. nbutyl, isobutyl and tert-butyl), pentyl and its isomers, hexyl and its isomers, and the like.

The term C _1-4 alkyl as a group or part of a group refers to a hydrocarbyl radical of the formula C _n H _{2n + 1} , where n is a number in the range from 1 to 4. C _1-4 Alkyl groups contain from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably from 1 to 2 carbon atoms. C _1-4 Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used in this document after a carbon atom, the subscript means the number of carbon atoms that a named group may contain.

_C1-4 alkyl includes all linear or branched alkyl groups with 1-4 carbon atoms and therefore includes methyl, ethyl, n-propyl, isopropyl, 2-methylethyl, butyl and its isomers (e.g. n-butyl, isobutyl and tert-butyl) and the like.

The term C _1-3 αalkyl as a group or part of a group refers to a hydrocarbyl radical of the formula C _n H _{2n + 1} , where n is a number in the range from 1 to 3. C _1-3 Alkyl groups contain from 1 to 3 carbon atoms, preferably from 1 to 2 carbon atoms. C _1-3 Alkyl groups can be linear or branched and may be substituted as indicated herein. When a subscript is used in this document after a carbon atom, the subscript means the number of carbon atoms that a named group may contain. C _1-3 Alkyl includes all linear or branched alkyl groups of 1 to 3 carbon atoms and therefore includes methyl, ethyl, n-propyl, isopropyl, 2-methylethyl, and the like.

In one embodiment, the expression at least one heteroatom is limited to 1, 2, or 3 heteroatoms, in a particular embodiment 1 or 2 heteroatoms, in a more specific embodiment 1 heteroatom.

4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) _p and N (as occurs, for example, in the definitions of Het ¹ , Het ^a , rings A and rings B); in a specific embodiment, is a 4-, 5- or 6-membered saturated heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, S (= O) p and N; in a more specific embodiment, a 4-, 5- or 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from O, S, S (= O) p and N.

Examples of a 4-, 5-, or 6-membered saturated heterocyclyl containing at least one heteroatom each independently selected from O, S, S (= O) p and N include, without limitation, azetidinyl, morpholinyl, piperidinyl, pyrrolidinyl, 1,1-dioxothietanyl, 1,1-dioxothiomorpholinyl, piperazinyl, dioxolanyl, oxazolidinyl, oxetanyl, tetrahydrofuranyl and the like.

Het ¹ and Het ^a can be attached to the remainder of the molecule of formula (I) through any available ring carbon or ring heteroatom, if necessary, unless otherwise indicated.

It will be understood that if two substituents on the same carbon atom from the definition of Het ¹ or Het ^a are taken together to form, together with the common carbon atom to which they are attached, ring A or ring B, respectively, a spiro moiety is formed.

For example, if Het ¹ is 1-piperidinyl, in which two substituents on the β carbon are taken together to form, together with the common carbon to which they are attached, ring B, the following spiro moiety is formed:

in particular, if, in the above example, ring A is 3-azetidinyl, the following spiro moiety is formed:

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Examples of such spiro moieties include, but are not limited to:

etc.

In all cases where substituents are represented by a chemical structure, ___ means a bond for attachment to the remainder of the molecule of formula (I).

Whenever one of the ring systems is substituted by one or more substituents, these substituents may, unless otherwise indicated or clearly indicated by the context, replace any hydrogen atom bonded to a carbon or nitrogen atom of the ring system.

The term “subject” as used herein refers to an animal, preferably a mammal (eg, a cat, dog, primate, or human), more preferably a human, who has been or has been the object of treatment, observation or experiment.

The term therapeutically effective amount, as used herein, means that amount of active compound or pharmaceutical agent that elicits a biological or medical response in the tissue system in an animal or human that a researcher, veterinarian, physician or other clinician seeks to obtain, which includes relief or relief symptoms of the disease or disorder to be treated.

The term composition is intended to encompass a product containing specified ingredients in specified amounts, as well as any product that is obtained, directly or indirectly, from combinations of specified ingredients in specified amounts.

The term treatment, as used herein, is intended to mean all methods that may involve slowing, disrupting, suppressing, or stopping the progression of a disease, but does not necessarily mean the complete elimination of all symptoms.

The term compounds of the present invention as used herein is intended to include compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates.

Any chemical formula used herein in which bonds are shown only as solid lines and not as solid wedge-shaped or dashed wedge-shaped bonds, or otherwise shown as having a particular configuration (e.g., R, S) near one or more atoms , provides each possible stereoisomer or mixture of two or more stereoisomers.

Above and below, in this document, the term compound of formula (I) is meant to include its stereoisomers and tautomeric forms.

The terms stereoisomers, stereoisomeric forms, or stereochemically isomeric forms above or below are used interchangeably herein.

The present invention includes all stereoisomers of the compounds of the present invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

Enantiomers are stereoisomers that are not overlapping mirror images of each other. A 1: 1 mixture of a pair of enantiomers is a racemate or racemic mixture.

Atropisomers (or atropisomers) are stereoisomers that have a particular spatial configuration resulting from limited rotation around a single bond due to significant steric hindrance. It is assumed that all atropisos

6,037871 dimensional forms of the compounds of formula (I) are included within the scope of the present invention.

Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If the compound contains a double bond, then the substituents can be in the E- or Z-configuration. The substituents on bivalent cyclic (partially) saturated radicals can be in either the cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E-isomers, Z-isomers, cis-isomers, trans-isomers, and mixtures thereof whenever possible from a chemical point of view.

The meanings of all these terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E-isomers, Z-isomers, cis-isomers, trans-isomers, and mixtures thereof, are known to the person skilled in the art.

The absolute configuration is determined in accordance with the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is defined as either R or S. Isolated stereoisomers, the absolute configuration of which is unknown, may be designated as (+) or (-) depending on the direction in which they rotate the plane of polarization of the light. For example, isolated enantiomers, the absolute configuration of which is unknown, can be designated as (+) or (-) depending on the direction in which they rotate the plane of polarization of light.

When a specific stereoisomer is indicated, it means that said stereoisomer is substantially free of other stereoisomers, i. E. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1% of other stereoisomers. Thus, if a compound of formula (I) is, for example, indicated as (R), this means that the compound is substantially free of the (S) isomer; if a compound of formula (I), for example, is indicated as E, this means that the compound is substantially free of the Z-isomer; when a compound of formula (I), for example, is indicated as cis, this means that the compound is substantially free of the trans isomer.

Certain compounds of formula (I) may also exist in their tautomeric form. It is contemplated that such forms, because they may exist, are included within the scope of the present invention. It follows from this that one compound can exist in both stereoisomeric and tautomeric forms.

For example, a person skilled in the art will understand that if R ¹ is

^: , then i is also included in the scope of the present invention.

For therapeutic use, the salts of the compounds of formula (I), their N-oxides and solvates are those whose counterion is pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether they are pharmaceutically acceptable or not, are included within the scope of the present invention.

The pharmaceutically acceptable addition salts as referred to hereinabove or below are contemplated to include the therapeutically active non-toxic acid and base addition salt forms that the compounds of formula (I), their N-oxides and solvates can form. Pharmaceutically acceptable acid addition salts can be readily prepared by treating the base form with such a suitable acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, for example hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propane, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely, these salt forms can be converted by treatment with an appropriate base to the free base form.

The compounds of formula (I), their N-oxides and solvates containing an acidic proton can also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Suitable basic salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, the four isomers of butylamine, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethyladinolamine, tripropliquine benzathine salts,

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N-methyl-D-glucamine, hydrabamine and salts with amino acids such as, for example, arginine, lysine and

etc. Conversely, the salt form can be converted by acid treatment to the free acid form.

The term solvate includes the hydrates and solvent addition forms which the compounds of formula (I) can form, as well as their N-oxides and pharmaceutically acceptable addition salts. Examples of such forms are, for example, hydrates, alcoholates and the like.

The compounds of the present invention obtained in the processes described below can be synthesized as mixtures of enantiomers, in particular racemic mixtures of enantiomers, which can be separated from each other following art-known separation procedures. The method of separating enantiomeric forms of compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the corresponding starting materials, provided that the reaction proceeds stereospecifically. If a specific stereoisomer is desired, it is preferred that said compound be synthesized using stereospecific methods of preparation. These methods will advantageously use enantiomerically pure starting materials.

Within the framework of the present invention, an element, in particular when referred to in relation to a compound of formula (I), includes all isotopes and mixtures of isotopes of this element, either naturally occurring or synthetically obtained, or with a natural isotopic composition or in isotopically enriched form. Radiolabeled compounds of formula (I) may contain a radioactive isotope selected from the group consisting of ² H, ³ H, ⁿ C, ¹⁸ F, ¹²² I, ¹²³ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. Preferably, the radioactive isotope is selected from the group consisting of ² H, ³ H, 11C and ¹⁸ F. More preferably, the radioactive isotope is ² H.

In particular, deuterated compounds are intended to be included within the scope of the present invention.

In one embodiment, the present invention relates to novel compounds of formula (I), tautomers and stereoisomeric forms thereof, wherein

R ¹ is hydrogen, —C (= O) OH, —C (= O) NH ₂ , —NH ₂ .

R ² represents < ³ · ³ , ^{he or} ;

R ³ is C1-4 alkyl; C1-4alkyl substituted on the same carbon with one —OH and one Het ¹ ; or C1-4alkyl substituted with one substituent selected from the group consisting of fluoro, —OH, —NH ₂ , —O- (C = O) —C _1-4 alkyl, - (C = O) —O — C _{1 -4} alkyl, -NH- (C = O) -C _1-4 alkyl, -NH- (SO2) -C1-4 alkyl, -N (CH3) -C1-4 alkyl-SO2-CH3, -NH-C1-4 alkyl -SO2-CH3, -N (C ^ -C ^ alkyl-OH

- (C = O) -NH-C1-4alkyl-OH, -0- (C = 0) -CH (NH2) -C1-4alkyl, -0- (C = 0) -CH (NH2) -C1-4alkyl -Ar, ^ο , NH-C1-4alkyl-OH, Het ¹ , -O-C (= O) -C1-4alkyl-Het ¹ , -C (= O) -Het ¹ and -NH-C (= O) -Het ¹ ;

R ^4a is hydrogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more substituents, each independently selected from the group consisting of —OH and —NR5R ⁶ ;

R ^4b is hydrogen, halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents; or

R ^4a and R ^4b are taken together to form, together with the phenyl ring to which they are attached, the structures of formula (a-1), (a-2), (a-3), (a-4) or (a-5 );

X is —NH—, —O—, —N (C _1-3 alkyl) - or —N (hydroxy — C _1-3 alkyl) -;

both R ⁷ are hydrogen;

both R ⁸ are hydrogen;

R ⁵ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with one —OH;

R ⁶ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with one —OH;

wherein Het ¹ is a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) _p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, —NH2, C _1-4 alkyl, —S (= O) ₂ - C _1-6 alkyl, —C _1-4 alkyl-S (= O) ₂ —C _1-6 alkyl, hydroxyl, C _1-4 alkyloxy, fluoro, cyano, and C _1-4 alkyl substituted with one hydroxy; or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring A;

- 8 037871 wherein ring A is cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each of which is independently selected from O, S, S (= O) _p and N; wherein said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl are optionally substituted with one or two C _1-4 alkyl substituents, one C _1-4 alkyl substituent and one substituent, representing hydroxy, or one substituent representing hydroxy;

p is 1 or 2;

and their N-oxides, pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), tautomers and stereoisomeric forms thereof, wherein

R ¹ is hydrogen or —NH ₂ ;

About '' IT

R ² represents ^or '

R ³ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and Het ¹ ;

R ^4a is C _1-4 alkyl;

R ^4b is halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents;

or R ^4a and R ^4b are taken together to form, together with the phenyl ring to which they are attached, the structure of formula (a-2);

X is —N (C _1-3 αalkyl) - or —N (hydroxy-C _1-3 alkyl) -;

both R ⁷ are hydrogen;

both R ⁸ are hydrogen;

Het ¹ is a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from S (= O) p and N; wherein said 4-, 5, or 6-membered saturated heterocyclyl is optionally substituted with one or two hydroxyl substituents; or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring A;

wherein Ring A is cyclobutyl optionally substituted with one hydroxy substituent;

p equals 2;

and their N-oxides, pharmaceutically acceptable addition salts and solvates.

In one embodiment, the present invention relates to novel compounds of formula (I), tautomers and stereoisomeric forms thereof, wherein

R ¹ is hydrogen or —NH ₂ ;

R ² represents or _;

R ³ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and Het ^1a ;

R ^4a is C _1-4 alkyl;

R ^4b is halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents; or

R ^4a and R ^4b are taken together to form, together with the phenyl ring to which they are attached, the structures of formula (a-2);

X is —N (C _1-3 αalkyl) - or —N (hydroxy-C _1-3 alkyl) -;

both R ⁷ are hydrogen;

both R ⁸ are hydrogen;

Het ^{1a is} attached to the R ³ residue via a ring nitrogen atom and represents a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from S (= O) _p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two hydroxyl substituents; or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring A;

wherein Ring A is cyclobutyl optionally substituted with one hydroxy substituent;

p equals 2;

- 9 037871 and their N-oxides, pharmaceutically acceptable addition salts and solvates.

Another embodiment of the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply:

(i) R ¹ is hydrogen or —NH ₂ ;

(ii) R ² is (iii) R ³ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and Het ¹ ;

(iv) R ^4a is C _1-4 alkyl;

R ^4b is halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents; or R ^4a and R ^4b are taken together to form, together with the phenyl ring to which they are attached, the structure of formula (a-2);

(v) X is -N (C _1-3 alkyl) - or -N (hydroxy-C _1-3 alkyl) -;

(vi) both R ⁷ are hydrogen;

(vii) both R ⁸ are hydrogen;

(viii) Het ¹ is a 4-, 5-, or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from S (= O) _p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two hydroxyl substituents; or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring A;

(ix) Ring A is cyclobutyl optionally substituted with one hydroxy substituent;

(x) p equals 2.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ¹ is —NH 2;

R ² represents

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ¹ is hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is C _1-4 alkyl or C _1-4 alkyl substituted with one —OH.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is C _1-4 alkyl substituted with one Het ¹ ; in particular, where Het ^{1 is} attached to the residue R ³ through a ring nitrogen atom (Het ^1a ).

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ^4a is hydrogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more substituents, each independently selected from the group consisting of —NR5R ⁶ and Het ^a ;

R ^4b is hydrogen, halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ^4a is hydrogen, C1-4 alkyl, Het ^a, or C1-4 alkyl substituted with one or more substituents, each independently selected from the group consisting of —OH, —NR5R ⁶ and Het ^a ;

- 10 037871

R ^4b is hydrogen, halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ^4a is C _1-4 alkyl; in particular R ^4a is methyl;

R ^4b is C _1-4 alkyl substituted with one or more halogen substituents, in particular R ^4b is CF3.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ^4a is C _1-4 alkyl, in particular R ^4a is methyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ^4a is hydrogen, C1- 4alkyl, Het ^a or C1-4alkyl substituted with one substituent selected from the group consisting of —OH, —NR ⁵ R ⁶ and Het ^a .

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ^4b is C _1-4 alkyl substituted with one or more halogen substituents, in particular R ^4b is CF3.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ^4a and R ^4b are other than hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ^4a and R ^4b are taken together with forming, together with the phenyl ring to which they are attached, the structures of the formula (a-1), (a-2), (a-3), (a-4) or (a-5), in particular the structure of the formula (a -2) or (a-4); more specifically, structures of formula (a-2).

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ^4a is C1-4 alkyl, Het ^a or C1-4 alkyl substituted with one or more substituents each independently selected from the group consisting of —OH, —NR ⁵ R ⁶ and Het ^a ;

R ^4b is hydrogen, halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents;

or R ^4a and R ^4b are taken together to form, together with the phenyl ring to which they are attached, the structure of formula (a-2).

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ^4a is C1-4 alkyl, Het ^a or C1-4 alkyl substituted with one or more substituents each independently selected from the group consisting of —OH, —NR ⁵ R ⁶ and Het ^a ;

R ^4b is C _1-4 alkyl or C _1-4 alkyl substituted with one or more halogen substituents.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ^4a is C1-4 alkyl, Het ^a or C1-4 alkyl substituted with one or more substituents each independently selected from the group consisting of —OH, —NR ⁵ R ⁶ and Het ^a ;

R ^4b is C _1-4 alkyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ^4a is C1-4 alkyl, Het ^a or C1-4 alkyl substituted with one or more substituents each independently selected from the group consisting of —OH, —NR ⁵ R ⁶ and Het ^a ;

R ^4b is C _1-4 alkyl or C _1-4 alkyl substituted with one or more halogen substituents; or

R ^4a and R ^4b are taken together to form, together with the phenyl ring to which they are attached, the structure of formula (a-2).

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ³ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of fluoro, OH, —NH2, —O- (C = O) —C _1-4 alkyl, —NH - (C = O) -C _1-4 alkyl, -NH- (SO ₂ ) -C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , -NH-C _1-4 alkyl-SO ₂ -CH ₃ , -N (CH ₃ ) -C _1-4 alkyl-OH, o

· '' Nh ₂

- (C = O) -NH-C1-4alkyl-OH, -O- (C = O) -CH (NH2) -C1-4alkyl, -O- (C = O) -CH (NH2) -C1-4alkyl -Ar, o and -NH-C _1-4 alkyl-OH.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ³ is C1-4 alkyl; -CH (OH) -CH2-R ^q or C1-4alkyl substituted with one substituent selected from the group consisting of fluoro, -OH, -NH2, -NH- (C = O) -C _1-4 alkyl, -NH - (SO ₂ ) -C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , -NH-C _1-4 alkyl-SO ₂ -CH ₃ , -N (CH ₃ ) -C _1-4 alkyl-OH, - (C = O) -NH-C _1-4 alkyl-OH and -NH-C _1-4 alkyl-OH;

R ^q is —OH or —NH2.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ³ is C _1-4 alkyl substituted with one substituent selected from the group consisting of fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, -NH- (C = O ) -C _1-4 alkyl, -NH- (SO ₂ ) -C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , -NH-C _1-4 alkyl- SO ₂ -CH ₃ , -N (CH ₃ ) -C _1-4 alkyl-OH, - (C = O) -NH-C _1-4 alkyl-OH,

-O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl, -O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar, o and -NH-C _1-4 alkyl-OH.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, -NH- (C = O) - C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , · - '' NH,

-NH-C _1-4 alkyl-SO ₂ -CH ₃ , -O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl, -O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar, o and

-NH-C _1-4 alkyl-OH.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is —CH (OH ) -CH2-R ^q or C1-4 alkyl substituted with one substituent selected from the group consisting of fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, -NH- (C = O) -C _1-4 alkyl, -NH- (SO ₂ ) -C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , -NH-C _1-4 alkyl -SO ₂ -CH ₃ , -N (CH ₃ ) -C _1-4 alkyl-OH, - (C = O) -NH-C _1-4 alkyl-OH,

-O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl, -O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar, o and -NH-C _1-4 alkyl-OH.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is C _1-4 alkyl substituted with one substituent as defined in any of the other embodiments.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ² is

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ² is

- 12 037871

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is C _1-4 alkyl substituted with one substituent representing —OH; in particular R ³ is —CH2 — OH., In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the others embodiments, where R ¹ is

is -C (= O) NH ₂ , -NH2,

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ¹ is

-C (= O) NH2, -NH2,

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ¹ is

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ¹ is —C (= O) OH, -C (= O) NH ₂ or -NH2.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ¹ is —C (= O) NH2 or -NH2.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ¹ is —NH 2.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ¹ is hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ¹ is other than hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Rq is fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, -NH- (C = O) -C _1-4 alkyl,

-NH- (SO ₂ ) -C _1-4 α-alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , -NH-C _1-4 α-alkyl-SO ₂ -CH ₃ , -N (CH ₃ ) -C _1-4 alkyl-OH, -O- (C = O) -CH (NH ₂ ) -C _1-4 α-alkyl or -NH-C _1-4 alkyl-OH.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ^q is

- 13 037871

—OH or —NH ₂ , in particular where Rq is —NH ₂ .

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ³ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of fluoro, -OH, -O- (C = O) -C _1-4 alkyl, -NH- ( SO ₂ ) -C _1-4 αalkyl, -N (CH3) -C1-4αalkyl-SO2-CH3, -NH-C1-4 alkyl-SO2-CH3, -N (CH3) -C1-4alkyl-OH, - (C = O) -NH-C1-4 alkyl-OH and -NH-C _1-4 α-alkyl-OH;

in particular, where R ³ is C _1-4 alkyl or C _1-4 α-alkyl substituted with one substituent selected from the group consisting of fluoro, —OH, —N (CH ₃ ) —C _1-4 alkyl-SO ₂ —CH ₃ , —NH — C _1-4 αalkyl — SO ₂ —CH ₃ , —N (CH ₃ ) —C _1-4 alkyl-OH and —NH — C _1-4 alkyl-OH;

more specifically, where R ³ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of fluoro and —OH;

even more specifically, where R ³ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent representing —OH;

even more specifically, where R ³ is C _1-4 alkyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein each Het ^{a is} independently

mo is

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein each Het ^{a is} independently 4- , 5- or 6-membered saturated heterocyclyl containing one or two heteroatoms, each of which is independently selected from O, S (= O) _p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy and C _1-4 alkyl substituted with one hydroxy;

p equals 1 or 2.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein both R ⁷ are hydrogen and where both R ⁸ are hydrogen.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein both R ⁷ substituents are the same and selected from the group consisting of hydrogen, fluorine and methyl; and both R ⁸ are the same and are selected from the group consisting of hydrogen and methyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ² is

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ² is

- 14 037871

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ² is

, limited to

•

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ² is

or •

limited accordingly

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ³ is C1.4 alkyl substituted with one substituent selected from the group consisting of Het ^1a , —C (= O) —Het ¹ and —NH — C (= O) —Het ^1b ; or C1.4 alkyl substituted on the same carbon with one —OH or one Het ^1b ;

Het ¹ is a 4-, 5-, or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) _p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, —NH2, C1. ₄ alkyl, -S (= O) ₂ -C ₁ . ₆ alkyl, -C ₁ . ₄ alkyl-S (= O) ₂ -C ₁ . ₆ alkyl, hydroxy and C1. ₄ alkyl substituted with one hydroxy; or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring A;

Het ^{1a is} defined as Het ¹ , but with the proviso that Het ^{1a is} always attached to the R ³ residue via a ring nitrogen atom;

Het ^{1b is} defined as Het ¹ , but with the proviso that Het ^{1b is} always attached to R ³ via a ring carbon.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ³ is C1.4 alkyl substituted with one substituent selected from the group consisting of Het ^1a , —OC (= O) —C1. ₄ alkyl-Het ^1a , -C (= O) -Het ¹ and -NH-C (= O) -Het ^1b ; -CH (OH) -CH2-Het ^1a ; or C1.4 alkyl substituted on the same carbon with one —OH and one Het ^1b ;

Het ¹ is a 4-, 5-, or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, —NH2, C1. ₄ alkyl, -S (= O) ₂ -C ₁ . ₆ alkyl, -C ₁ . ₄ alkyl-S (= O) ₂ -C ₁ . ₆ alkyl, hydroxy and C1. ₄ alkyl substituted with one hydroxy; or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl 15,037871 are taken together to form, together with the common carbon atom to which they are attached, ring A;

Het ^{1a is} defined as Het ¹ , but with the proviso that Het ^{1a is} always attached to the R ³ residue via a ring nitrogen atom;

Het ^{1b is} defined as Het ¹ , but with the proviso that Het ^{1b is} always attached to R ³ via a ring carbon.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ¹ is other than —C ( = O) OH.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ³ is C1-4 alkyl substituted with one substituent selected from the group consisting of Het ¹ , —C (= O) —Het ¹ and —NH — C (= O) —Het ^1, or C1-4 alkyl substituted at one and the same carbon atom with one -OH and one Het ¹ .

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is C1-4 alkyl, substituted with one substituent selected from the group consisting of Het ¹ , -C (= O) -Het ¹ and -NH-C (= O) -Het ¹ ; -CH (OH) -CH2-Het ¹ ; or C1-4alkyl substituted on the same carbon with one —OH and one Het ¹ .

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is C1-4 alkyl, substituted with one substituent selected from the group consisting of Het ¹ , -OC (= O) -C1-4alkyl-Het ¹ , -C (= O) -Het ¹ and -NH-C (= O) -Het ¹ or - CH (OH) -CH ₂ -Het ¹ .

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is C _1-4 alkyl substituted with one substituent selected from the group consisting of Het ¹ , —C (= O) —Het ^1, and —NH — C (= O) —Het ¹ .

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is C1-4 alkyl, substituted with one substituent selected from the group consisting of Het ¹ and —C (= O) —Het ¹ ; in particular, R ³ is C1-4 alkyl substituted with one Het ¹ .

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is C _1-4 alkyl substituted with one substituent selected from the group consisting of Het ¹ , —C (= O) —Het ^1, and —NH — C (= O) —Het ¹ .

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein R ³ is C1-4 alkyl, substituted with one substituent representing Het ¹ ; in particular R ³ _{is C 1-4} alkyl substituted with one substituent Het ^1a , where Het ^{1a is} defined as Het ¹ , but with the proviso that Het ^{1a is} always attached to C 1-4 alkyl via a ring nitrogen atom.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Het ¹ is 4-, 5 - or a 6-membered saturated heterocyclyl containing at least one heteroatom, each of which is independently selected from S (= O) p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of —NH2, C _1-4 alkyl, —S (= O) ₂ —C _{1 -6} alkyl, hydroxy, and C _1-4 alkyl substituted with one hydroxy; or two substituents on the same carbon atom of said 4-, 5 or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring A.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Het ¹ is 4-, 5 - or a 6-membered saturated heterocyclyl containing at least one heteroatom,

- 16 037871 each of which is independently selected from S (= O) p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of —NH2, C _1-4 alkyl, —S (= O) ₂ —C _{1 -6} alkyl, hydroxy, and C _1-4 alkyl substituted with one hydroxy.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Ring A is 4-, 5 -or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from S (= O) _p and N.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Ring A is cyclobutyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Ring A is cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each of which is independently selected from S (= O) _p and N; wherein said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl are optionally substituted with one hydroxy substituent.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Het ¹ is 4-, 5 - or a 6-membered saturated heterocyclyl containing at least one heteroatom, each of which is independently selected from O, S, S (= O) p and N; and two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring A.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Het ¹ is 4-, 5 - or a 6-membered saturated heterocyclyl containing at least one heteroatom, each of which is independently selected from O, S, S (= O) p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of —NH2, C _1-4 alkyl, —S (= O) ₂ —C _{1 -6} alkyl, -C _1-4 alkyl-S (= O) ₂ -C ₁₆ alkyl, hydroxy and C _1-4 alkyl substituted with one hydroxy.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Het ¹ is 4-, 5 - or a 6-membered saturated heterocyclyl containing at least one heteroatom, each of which is independently selected from O, S, S (= O) p and N; p equals 2.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Het ¹ is 4-, 5 - or a 6-membered saturated heterocyclyl containing one S (= O) p, and also containing one N; p equals 2.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Het ¹ is 4-, 5 - or a 6-membered saturated heterocyclyl containing one S (= O) p, and also containing one N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of —NH ₂ , C _1-4 alkyl, —S (= O) ₂ —C _1-6 alkyl, —C _1-4 alkyl-S (= O) ₂ —C _1-6 alkyl, hydroxy, and C _1-4 alkyl substituted with one hydroxy; p equals 2.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Het ¹ is co-

the battle ·

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or to any of them

17,037,871 subgroups as mentioned in any of the other embodiments, wherein Het ¹ is a coO / S — C 'moiety optionally substituted with one or two substituents, each independently selected from the group consisting of —NH ₂ , C _{1- 4} alkyl, —S (= O) ₂ —C _1-6 alkyl, —C _1-4 alkyl-S (= O) ₂ —C _1-6 alkyl, hydroxy, and C _1-4 alkyl substituted with one hydroxyl; in particular, optionally substituted with hydroxyl.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Het ¹ is

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ³ is C1-4 alkyl; -CH (OH) -CH2-R ^q or C1-4 alkyl substituted with one substituent selected from the group consisting of fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, - ( C = O) -O-C _1-4 alkyl, -NH- (C = O) -C _1-4 alkyl, -NH- (SO ₂ ) -C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , -NH-C _1-4 alkyl-SO ₂ -CH ₃ , -N (CH3) -C1-4 alkyl-OH, - (C = O) -NH-C1-4 alkyl -OH, -O- (C = O) -CH (NH2) -C1-4alkyl,

-O- (C = O) -CH (NH2) -C1-4alkyl-Ar, ° - -NH-C1-4alkyl-OH, Het ¹ and -C (= O) -Het1;

Het ¹ represents

OH I s ^ = o

......-- ^0H, 'OR.

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein (CH ₂ ) _n -Z ¹ ।-- (CHW

M - Het ¹ represents ⁷ ;

Z ¹ represents -NH-, -S-, -O- or -S (O) 2-; in particular Z ¹ is —S (O) 2-;

n is 0, 1, or 2;

m is 1, 2, or 3, provided that m is not 1 if n is 0.

In a specific embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Het ^{1 is} attached to the remainder of the molecule of formula ( I) via a nitrogen atom (Het ^1a ).

In a specific embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein Het ^{1 is} attached to the remainder of the molecule of formula ( I) via a carbon atom (Het ^1b ).

In a specific embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ³ is C1-4 alkyl; C1-4alkyl substituted on the same carbon with one —OH and one Het ¹ ; or C1-4alkyl substituted with one substituent selected from the group consisting of fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, - (C = O) -O-C _{1- 4} alkyl, -NH- (C = O) -C _1-4 alkyl, -NH- (SO ₂ ) -C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-sO ₂ -CH ₃ , -NH-C _1-4 alkyl-SO ₂ -CH ₃ , -N (CH ₃ ) -C _1-4 alkyl-OH,

- (C = O) -NH-C1-4alkyl-OH, -O- (C = O) -CH (NH2) -C1-4alkyl, -O- (C = O) -CH (NH2) -C1-4alkyl -Ar, -NH-C _1-4 alkyl-OH, Het ¹ and -C (= O) -Het ¹ ;

- 18 037871

Het ^{1 is} attached to the remainder of the molecule of formula (I) through a nitrogen atom (Het ^1a ).

In one embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ³ is C1-4 alkyl; -CH (OH) -CH2-R ^q or C1-4alkyl substituted with one substituent selected from the group consisting of fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, - ( C = O) -O-C _1-4 alkyl, -NH- (C = O) -C _1-4 alkyl, -NH- (SO ₂ ) -C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , -NH-C _1-4 alkyl-SO ₂ -CH ₃ ,

-N (CH ₃ ) -C _1-4 alkyl-OH, - (C = O) -NH-C _1-4 alkyl-OH, -O- (C = O) -CH (NH ₂ ) -C _{1- 4} alkyl,> jh,

-O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar, °, -NH-C _1-4 alkyl-OH, Het ¹ and -C (= O) -Het ¹ ;

Het ^{1 is} attached to the remainder of the molecule of formula (I) through a nitrogen atom (Het ^1a ).

In a specific embodiment, the present invention relates to such compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, as mentioned in any of the other embodiments, wherein

R ³ is C1-4 alkyl; -CH (OH) -CH2-R ^q ; C1-4alkyl substituted on the same carbon with one —OH and one Het ^1b ; or C _1-4 alkyl substituted with one substituent selected from the group consisting of fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, - (C = O) -O-C _1-4 alkyl, -NH- (C = O) -C _1-4 alkyl, -NH- (SO ₂ ) -C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ - CH ₃ , -NH-C _1-4 alkyl-SO ₂ -CH ₃ ,

- N (CH3) -C1-4alkyl-OH, - (C = O) -NH-C1-4alkyl-OH, -O- (C = O) -CH (NH2) -C1-4alkyl,

- ° '^ 44 _N h ₂

- O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar, °> -NH-C _1-4 alkyl-OH, Het ^1a , -OC (= O) -C _1-4 alkyl-Het ^1a ,

- C (= O) -Het ¹ and -NH-C (= O) -Het ^1b ;

R ^q is Het ^1a , fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, -NH- (C = O) -C _1-4 alkyl, -NH- (SO ₂ ) -C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , -NH-C _1-4 alkyl-SO ₂ -CH ₃ , -N (CH ₃ ) - C _1-4 alkyl-OH, .-% Χ ^η ·

- O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl, -O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar, o or -NH-C _1-4 alkyl-OH;

Het ¹ is a 4-, 5-, or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) _p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, —NH2, C _1-4 alkyl, —S (= O) ₂ - C _1- 6alkila, -C _1-4 alkyl-S (= O) ₂ -C _1- 6alkila, hydroxy and C _1-4 alkyl substituted with one hydroxy;

or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring A;

Het ^{1a is} defined as Het ¹ , but with the proviso that Het ^{1a is} always attached to the R ³ residue via a ring nitrogen atom;

Het ^{1b is} defined as Het ¹ , but with the proviso that Het ^{1b is} always attached to R ³ via a ring carbon.

All possible combinations of the above embodiments are intended to fall within the scope of the present invention.

Methods for preparing compounds of formula (I)

In this section, as in all other sections, unless the context indicates otherwise, references to formula (I) also include all other subgroups and examples thereof, as defined in this document.

General methods for the preparation of some representative examples of compounds of formula (I) are described herein and in the specific examples, and are generally prepared from starting materials that are either commercially available or obtainable by standard synthetic methods commonly employed by those skilled in the art. technology. It is intended that the following diagrams only represent examples of the present invention and in no way limit the present invention.

Alternatively, the compounds of the present invention can also be prepared using reaction protocols analogous to those described in the general schemes below, in combination with standard synthetic methods commonly used by those skilled in the art of organic chemistry.

One skilled in the art will understand that the reactions described in the Schemes may require protection of reactive functional groups, for example hydroxy, amino or carboxy groups, if required in the final product, in order to avoid their undesirable participation in the reactions. Traditional protecting groups can be used in accordance with standard practice. This is illustrated with specific examples. Protective groups can be removed by

- 19 037871 suitable subsequent step using methods known in the art.

One skilled in the art will appreciate that in the reactions described in the Schemes it may be appropriate or necessary to conduct the reaction under an inert atmosphere, such as, for example, N ₂ gas.

It will be obvious to a person skilled in the art that it may be necessary to cool the reaction mixture before processing the reaction product (refers to the number of manipulations necessary to isolate and purify the product (s) of a chemical reaction, such as, for example, quenching, column chromatography, extraction) ...

One of ordinary skill in the art will appreciate that heating the reaction mixture while stirring can increase the yield of the reaction. In some reactions, microwave heating can be used instead of traditional heating to shorten the overall reaction time.

One of ordinary skill in the art will appreciate that another sequence of chemical reactions shown in the Schemes below may also result in the desired compound of formula (I).

A person skilled in the art will understand that the intermediates and final compounds shown in the diagrams below can be further functionalized according to methods well known to the person skilled in the art.

In general, compounds of formula (I) where R ^{1 is} limited to hydrogen and where the remaining variables are as shown in formula (Ia) can be prepared according to the following Reaction Scheme 1 where W is a leaving group such as Cl or Br. All other variables in Scheme 1 are defined within the scope of the present invention.

Scheme 1

In Scheme 1, the following reaction conditions are applied:

1) in the presence of a suitable base, such as, for example, trimethylamine, in the presence of a suitable solvent, such as, for example, tetrahydrofuran;

2) in the presence of a suitable reagent, such as, for example, iron, in the presence of a suitable acid, such as, for example, hydrochloric acid or natural malic acid, in a suitable solvent, such as, for example, a mixture of ethanol and water at a suitable temperature, such as 100 ° C;

alternatively in the presence of a suitable catalyst such as Raney® Nickel at a hydrogen pressure such as, for example, 1 ATM, in a suitable solvent such as, for example, methanol;

3) in the case of R2H:

without solvent at a suitable temperature such as 100 ° C;

alternatively in the presence of a suitable ligand such as 2-dicyclohexylphosphino2 ', 6'-diisopropoxybiphenyl (Ruphos) or 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (DavePhos), a suitable catalyst such as, for example, tris- (dibenzylideneacetone) dipalladium (Pd ₂ dba ₃ ) or palladium acetate, a suitable base such as, for example, Cs ₂ CO ₃ , and a suitable solvent such as, for example, 2-methyl-2-butanol or dioxane at a suitable temperature such as, for example, 100 to 120 ° C;

in the case of R2B (OH) 2 or R2 (4,4,5,5-tetramethyl-1,3,2-dioxaborolane): in the presence of a suitable catalyst such as, for example, the dichloromethane adduct 1,1'-bis- (diphenylphosphino ) ferrocene palladium (P) dichloride or palladacycle RuPhos (chloropalladium, dicyclohexyl- [2- [2,6-di (propane-2yloxy) phenyl] phenyl] phosphane, 2-methoxy-2-methylpropane, 2-phenylethanamine), a suitable base, such as, for example, potassium phosphate, and a suitable solvent, such as, for example, a mixture of dioxane and water, at a suitable temperature ranging from 80 to 105 ° C;

- 20 037871

4) in a suitable solvent, such as, for example, 1-butanol, at a suitable temperature, such as, for example, the reflux temperature.

In general, compounds of formula (I), where R ^{1 is} limited to hydrogen and where the remaining variables are as shown in formula (Ib), (Ic), (Id), (I-e) and (If), can be obtained in according to the following Reaction Scheme 2, where W ¹ is a leaving group such as Cl, mesylate or tosylate, and where R ^x and R ^y are C1-4 alkyl and R ^z is C1-4αalkyl or phenyl, for example R ^x and R ^y are CH3 and R ^z is C (CH ₃ ) ₃ or phenyl. All other variables in Scheme 2 are defined within the scope of the present invention.

Scheme 2

In Scheme 2, the following reaction conditions are applied:

1) in a suitable solvent such as, for example, 1-butanol at a suitable temperature, such as, for example, the reflux temperature;

2) in the presence of a suitable reagent such as, for example, tetrabutylammonium fluoride (TBAF), hydrochloric acid or trifluoroacetic acid, in a suitable solvent such as THF, dioxane or dichloromethane;

3) in the presence of a suitable reagent such as, for example, di-tert-butyl azodicarboxylate, a suitable phosphine, such as, for example, triphenylphosphine, and in a suitable solvent such as, for example, THF;

4) in the presence of a suitable solvent such as ethanol at a suitable temperature such as 80 ° C;

5) in the case of acyl chloride: in the presence of a suitable base, such as, for example, diisopropylethylamine, and in a suitable solvent, such as, for example, dichloromethane; in the case of a carboxylic acid: in the presence of a suitable coupling reagent such as, for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, a suitable additive such as, for example, 1-hydroxybenzotriazole, a suitable base such as, for example , triethylamine, and in a suitable solvent such as, for example, a mixture of tetrahydrofuran (THF) and dichloromethane (DCM);

6) in the presence of a suitable base, such as, for example, triethylamine, in a suitable solvent, such as, for example, dichloromethane;

7) in the presence of a suitable coupling reagent such as, for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, a suitable additive such as, for example, 1-hydroxybenzotriazole, a suitable base such as, for example, triethylamine, and in a suitable solvent such as, for example, a mixture of THF and dichloromethane.

In general, compounds of formula (I) wherein R ^{1 is} limited to hydrogen and where the remaining variables are as shown in formula (Ig), (Ih) and (Ii) can be prepared according to the following Reaction Scheme 3 where Het ^{1a is} limited to Het ¹ attached via a nitrogen atom.

All other variables in Scheme 3 are defined within the scope of the present invention.

Scheme 3

R

R ^4a _R 4b (VIII) o o

Us. ^ Alkyl- ^ R ^H (XVIIa) O-C ^ alkyl

,. ₄ alkyl

Base, _N , which is alkali

-N

[D% C]. ₄ alkyl - ( ^z

N he

R ^4b (XVII)

Het ^1a (XVIII)

R ^4b (th)

NHM-C ^ alkyl-OH (XIX)

M-C ^ alkyl-OH

R ^4b (li)

In Scheme 3, the following reaction conditions are applied:

1) in a suitable solvent such as, for example, 1-butanol at a suitable temperature, such as, for example, the reflux temperature;

2) in the presence of a suitable base, such as, for example, sodium hydroxide or lithium hydroxide, in a suitable solvent, such as, for example, a mixture of tetrahydrofuran / water or a mixture of 2-methyltetrahydrofuran / water, at a suitable temperature, such as, for example, room temperature or 60 ° C;

3) in the presence of a suitable coupling reagent such as, for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, a suitable additive such as, for example, 1-hydroxybenzotriazole, a suitable base such as, for example, triethylamine, and in a suitable solvent such as, for example, a mixture of THF and dichloromethane;

4) in the presence of a suitable coupling reagent such as, for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, a suitable additive such as, for example, 1-hydroxybenzotriazole, a suitable base such as, for example, triethylamine, and in a suitable solvent such as, for example, a mixture of THF and dichloromethane.

In general, compounds of formula (I) wherein R ^{1 is} limited to hydrogen and where the remaining variables are as shown in formulas (Ij) and (Ik) can be prepared according to the following Reaction Scheme 4 where R ^{9 is} defined as H or CH3, and R ^{10 is} defined to be _{—C 1-4 alkyl — SO 2} —CH ₃ or —C 1-4 alkyl-OH. All other variables in Scheme 4 are defined within the scope of the present invention.

Scheme 4

- 22 037871

In Scheme 4, the following reaction conditions are applied:

1) in the presence of suitable reagents such as, for example, oxalyl chloride and dimethyl sulfoxide, a suitable base such as, for example, trimethylamine, in a suitable solvent such as, for example, DCM, at a suitable temperature ranging from -80 ° C to room temperature;

2) in the presence of a suitable reducing agent, such as, for example, sodium triacetoxyborohydride, in a suitable solvent, such as, for example, DCM;

3) in the presence of a suitable reducing agent, such as, for example, sodium triacetoxyborohydride, in a suitable solvent, such as, for example, DCM.

In general, compounds of formula (I) where R ^{1 is} limited to hydrogen and where the remaining variables are as shown in (I-1) can be prepared according to the following Reaction Scheme 5. All other variables in Scheme 5 are defined within the scope of the present invention.

Scheme 5

In Scheme 5, the following reaction conditions are applied: 1) in the presence of a suitable fluorinating reagent such as, for example, diethylaminosulfur trifluoride, in a suitable solvent, such as, for example, DCM.

In general, compounds of formula (I), where R ^{1 is} limited to hydrogen, and where the remaining variables are as shown in (Im), can be prepared according to the following reaction scheme “X my 6. In Scheme 6, R ¹¹ is - CH (NH ₂ ) -C _1-4 αlkyl, -CH (NH ₂ ) -C _1-4 alkyl-Ar ^NH 2 or

-C _1-4 alkyl-Het ¹ and PG ¹ is a protecting group such as, for example, tert-butoxycarbonyl or benzyloxycarbonyl.

All other variables are defined above or within the scope of the present invention.

Scheme 6

In Scheme 6, the following reaction conditions are applied:

1) in the presence of a suitable coupling reagent such as, for example, 1- [bis- (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide, a suitable additive, such as, for example, dimethylaminopyridine, a suitable base such as, for example, diisopropylethylamine, and in a suitable solvent such as, for example, DMF;

2) in the presence of an acid such as, for example, trifluoroacetic acid or hydrogen chloride, in a suitable solvent such as, for example, dichloromethane or methanol. Alternatively, in the presence of palladium-carbon in a suitable solvent such as methanol under a hydrogen atmosphere.

In general, compounds of formula (I) where R ^{1 is} limited to hydrogen and R ^{3 is} limited to CH2OH, CH ₂ -NR ⁹ R ¹⁰ and CH ² -Het ^1a (Het ^{1a is} limited to Het ¹ attached via a nitrogen atom) and where the remaining variables are as shown in formula (I-aa), (I-ba), (I-ka) and (I-ja) can be obtained according to the following reaction scheme 7. All other variables are defined above or within the scope of the present invention.

- 23 037871

Scheme 7

In Scheme 7, the following reaction conditions were used:

1) in a suitable solvent, such as, for example, dioxane, at a suitable temperature, such as, for example, the reflux temperature;

2) in the presence of a suitable reducing agent, such as, for example, sodium borohydride, in a suitable solvent, such as, for example, methanol;

3) in the presence of a suitable reducing agent, such as, for example, sodium triacetoxyborgydride, in a suitable solvent, such as, for example, DCM;

4) in the presence of a suitable reducing agent, such as, for example, sodium triacetoxyborohydride, in a suitable solvent, such as, for example, DCM.

In general, compounds of formula (I) where R ^{1 is} limited to hydrogen and Het ^{1a is} limited to Het ¹ attached via a nitrogen atom, and the rest of the variables herein as shown in formula (In) can be prepared according to the following Reaction Scheme 8. All other variables are as defined above or within the scope of the present invention.

Scheme 8

In Scheme 8, the following reaction conditions are applied:

1) at a suitable temperature, such as, for example, 0 or -78 ° C, in a suitable solvent, such as, for example, THF.

In general, compounds of formula (I) where R ^{1 is} limited to hydrogen and where the remaining variables are as shown in (I-o), (I-p) and (Iq) can be prepared according to the following Reaction Scheme 9. All other variables are defined above or within the scope of the present invention.

- 24 037871

Scheme 9

In Scheme 9, the following reaction conditions are applied:

1) in the presence of a suitable reagent, such as, for example, trimethylsulfonium iodide, in the presence of a suitable base, such as, for example, potassium hydroxide, in a suitable solvent, such as, for example, a mixture of acetonitrile and water, at a suitable temperature, such as, for example , 60 ° C;

2) in the presence of a suitable base, which is an alkali, such as, for example, sodium hydroxide, in a suitable solvent, such as, for example, a mixture of dioxane and water, at a suitable temperature, such as, for example, 80 ° C;

3) in a suitable solvent, such as, for example, acetonitrile or dimethylformamide, at a suitable temperature, such as, for example, 80 ° C, optionally under plugging conditions;

4) in a suitable solvent, such as, for example, acetonitrile or dimethylformamide, at a suitable temperature, such as, for example, 80 ° C, optionally under plugging conditions.

In general, compounds of formula (I) wherein R ¹ is —NH ₂ and where the remaining variables are as shown in formula (Ir) can be prepared according to the following Reaction Scheme 10 wherein W ³ is a leaving group such as Cl, Br or I. All other variables are as defined above or within the scope of the present invention.

Scheme 10

In Scheme 10, the following reaction conditions are applied:

1) in the presence of a nitrating agent, such as, for example, nitric acid, in a suitable solvent, such as, for example, sulfuric acid, at a suitable temperature, such as, for example, 10 ° C;

- 25 037871

2) in a suitable solvent, such as, for example, sulfuric acid at a suitable temperature, such as, for example, 100 ° C;

3) in the presence of a suitable reagent, such as, for example, iron, in the presence of a suitable acid, such as, for example, hydrochloric acid or acetic acid, in a suitable solvent, such as, for example, a mixture of ethanol and water, at a suitable temperature, such as 100 ° C;

4) in the presence of a suitable acid, such as, for example, hydrochloric acid, in a suitable solvent, such as, for example, ethanol, at a suitable temperature, such as, for example, 100 ° C;

5) in the presence of a suitable base, such as, for example, potassium carbonate, in a suitable solvent, such as, for example, acetonitrile, at a suitable temperature, such as, for example, 85 ° C;

6) in a sealed tube in the presence of a suitable catalyst, such as, for example, palladium acetate, in the presence of a suitable ligand, such as, for example, 2,2'-bis- (diphenylphosphino) 1,1'-binaphthyl, in the presence of a suitable base,

7) in the case of R2H: in the presence of a suitable such as, for example, cesium carbonate, in a suitable solvent such as, for example, dioxane, at a suitable temperature, such as, for example, 100 ° C; a ligand such as 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (DavePhos), a suitable catalyst such as, for example, palladium acetate, a suitable base such as, for example, Cs ₂ CO ₃ , and a suitable solvent such as, for example, dioxane, when a suitable temperature such as, for example, 120 ° C;

in the case of R2B (OH) 2 or R2 (4,4,5,5-tetramethyl-1,3,2-dioxaborolane): in the presence of a suitable catalyst such as, for example, the dichloromethane adduct dichloro (1,1'-bis- (phenylphosphino) ferrocene) palladium (P) or palladacycle RuPhos, a suitable base such as, for example, potassium phosphate, and a suitable solvent such as, for example, a mixture of dioxane and water, at a suitable temperature ranging from 80 to 105 ° C;

8) in the presence of a suitable acid, such as, for example, hydrochloric acid, in a suitable solvent, such as, for example, tetrahydrofuran (THF).

In general, compounds of formula (I) wherein R ^{1 is} limited to R ^1a being

: : or :

'' '' and where the rest of the variables are as shown in formula (Is) can be prepared according to the following Reaction Scheme 11. In Scheme 11, PG is defined as a protecting group such as, for example, N, N-dimethylsulfonamidyl or 2 -tetrahydropyranyl fragment. All other variables in Scheme 11 are defined above or within the scope of the present invention.

Scheme 11

R ² H (V)

(XXXX) (ks)

In Scheme 11, the following reaction conditions were used:

1) in the case of (PG) R ^1a B (OH) 2 or (PG) R ^1a (4,4,5,5-tetramethyl-1,3,2-dioxaborolane): in the presence of a suitable catalyst such as, for example, dichloromethane adduct of dichloro (1,1'-bis (diphenylphosphino) ferrocene) palladium (II), a suitable base such as, for example, potassium carbonate, and a suitable solvent such as, for example, a mixture of dioxane and water at a suitable temperature such such as at 100 ° C;

in the case of R ^1a (PG): first in the presence of zinc chloride, a suitable deprotonating agent such as, for example, butyllithium, a suitable solvent such as, for example, THF, at a suitable temperature, such as, for example, -78 ° C, followed by adding this solution to a mixture of intermediate (XXXXVI), optionally in solution in THF, and a suitable catalyst such as, for example, Pd (PPh ₃ ) 4, heating at a suitable temperature in the range of 60-100 ° C;

2) in the case of R ² H:

without solvent at a suitable temperature such as 100 ° C;

alternatively in the presence of a suitable ligand such as 2-dicyclohexylphosphino2 ', 6'-diisopropoxybiphenyl (RuPhos), a suitable catalyst such as, for example, tris (dibenzylideneacetone) dipalladium (Pd ₂ dba ₃ ), a suitable base such as, for example , Cs ₂ CO ₃ , and a suitable solvent such as, for example, 2-methyl-2-butanol, at a suitable temperature, such as, for example, 100-120 ° C;

in the case of R ₂ B (OH) ₂ or R ₂ (4,4,5,5-tetramethyl-1,3,2-dioxaborolane): in the presence of a suitable catalyst such as, for example, the dichloromethane adduct dichloro (1,1 ' -bis- (phenylphosphino) ferrocene) palladium (P) or RuPhos palladacycle, a suitable base such as, for example, potassium phosphate, and a suitable solvent such as, for example, a mixture of dioxane and water, at a suitable temperature ranging from 80 ° C to 105 ° C;

3) in the presence of a suitable acid, such as, for example, p-toluenesulfonic acid, hydrochloric acid or trifluoroacetic acid, in a suitable solvent such as, for example, dioxane, methanol or dichloromethane, at a suitable temperature, such as, for example, 50 or 100 ° C.

In general, compounds of formula (I) wherein R ¹ is —COOH and where the remaining variables are as shown in formula (Iu); and compounds of formula (I) wherein R ¹ is —CONH2 and where the remaining variables are as shown in formula (Iv) can be prepared according to the following Reaction Scheme 12, where all other variables are as defined above or according to the volume of the present invention.

Scheme 12

(l-v)

In Scheme 12, the following reaction conditions are applied:

1) in the presence of a suitable catalyst, such as, for example, Pd (PPh3) 4, a suitable base, such as, for example, triethylamine (Et ₃ N), and a suitable solvent, such as, for example, methanol or ethanol, at a suitable temperature, such as, for example, at 100 or 120 ° C;

2) in the presence of a suitable base, such as, for example, lithium hydroxide monohydrate, and a suitable solvent or solvent mixture, such as, for example, a THF / water or MeOH / water mixture.

3) in a suitable solvent such as, for example, methanol, at a suitable temperature, such as, for example, 65 ° C, and in a sealed vessel.

In all of these methods of preparation, the reaction products can be isolated from the reaction medium and, if necessary, further purified in accordance with techniques generally known in the art, such as, for example, extraction, crystallization, trituration and chromatography.

Chirally pure forms of the compounds of formula (I) form a preferred group of compounds. It follows from this that chirally pure forms of intermediates and their salt forms are particularly useful in the preparation of chirally pure compounds of formula (I). Enantiomeric mixtures of intermediates are also useful in the preparation of compounds of formula (I) with the corresponding configuration.

- 27 037871

Pharmacology.

The compounds of the present invention have been found to inhibit kinase activity

3Κβ and optionally also have PI3Kδ inhibitory activity.

Thus, it is expected that the compounds according to the present invention or pharmaceutical compositions based on them may be useful for the treatment or prevention, in particular treatment, of diseases such as cancer, autoimmune disorders, cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, allergies, pancreatitis, asthma, multiple organ failure, kidney disease, platelet aggregation, impaired sperm motility, transplant rejection, tissue rejection, lung damage, etc.; in particular cancer.

Since the pharmaceutically active compounds of the present invention are active as PI3Ke inhibitors, they are characterized by therapeutic benefits in the treatment or prevention, in particular treatment, of susceptible neoplasms, in particular those neoplasms characterized by PTEN deficiency.

As used herein, the phrase PTEN-deficient or PTEN deficient should describe tumors deficient in the tumor suppressor function of PTEN (homologue of phosphatase and tensin). Such a deficiency includes a mutation in the PTEN gene, a reduction in the number or absence of PTEN proteins compared to wild-type PTEN, or a mutation or absence of other genes that lead to suppression of PTEN function.

A susceptible neoplasm, as used herein, refers to neoplasms that are responsive to treatment with a kinase inhibitor, and in particular, neoplasms that are responsive to treatment with a PI3Ke inhibitor.

Neoplasms that have been associated with inappropriate PTEN phosphatase activity, and in particular neoplasms that are characterized by a PTEN mutation, or an upstream PI3Ke kinase activator mutation, or overexpression of an upstream PI3Ke kinase activator, and thus are susceptible to treatment with a PI3Ke inhibitor. the art and include both primary and metastatic tumors and cancers. In accordance with one embodiment, the meaning of treating a susceptible neoplasm may be used interchangeably with the meaning of treating a cancer.

According to one embodiment, susceptible neoplasms include, but are not limited to, PTEN-deficient neoplasms listed below: (forms of glioma) of the brain, forms of glioblastoma, forms of leukemia, Bannan-Zonan syndrome, Cowden's disease, Lermitte-Duclos disease, breast cancer , edematous infiltrative breast cancer, coloreactic cancer, Wilma's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, melanoma, squamous cell carcinoma, ovarian cancer, cancer pancreas, prostate cancer, sarcoma, osteosarcoma, giant cell myelogenous tumor, thyroid cancer, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute neutrophilic chronic leukemia, acute myelogenous leukemia, acute myelogenous leukemia T-cell leukemia, plasmacytoma, immunoblastic large cell lymphoma, mantle cell lymphoma, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, lymphoma of Berkcuroblastoma, bladder cancer , cervical cancer, vulvar cancer, endometrial cancer, renal cell carcinoma, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, stomach cancer, nasopharyngeal cancer, cheek cancer, oral cancer, GIST (gastrointestinal stromal tumor ) and testicular cancer.

In an alternative embodiment, the term susceptible neoplasm encompasses hormone-resistant prostate cancer, non-small cell lung cancer, endometrial cancer, stomach cancer, melanoma, head and neck cancer, breast cancer, including triple negative phenotype breast cancer and glioma.

In one embodiment, the term susceptible neoplasm includes and is limited to: prostate cancer, in particular hormone-resistant prostate cancer.

The compounds of the present invention may also have therapeutic uses in sensitizing tumor cells to radiation therapy and chemotherapy.

Thus, the compounds of the present invention can be used as a radiosensitizer and / or chemosensitizer, or they can be administered in combination with another radiosensitizer and / or chemosensitizer.

The term radiosensitizer, as used herein, is defined as a molecule, preferably a low molecular weight molecule, that is administered to animals in therapeutically effective amounts to increase the sensitivity of cells to ionizing radiation and / or

- 28 037871 to improve the effectiveness of treatment of diseases that can be treated with ionizing radiation.

The term chemosensitizer, as used herein, is defined as a molecule, preferably a low molecular weight molecule, that is administered to animals in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and / or to increase the effectiveness of treating diseases that are treatable with chemotherapeutic agents.

Several mechanisms of the mode of action of radiosensitizers have been proposed in the literature, including radiosensitizers leading to cellular hypoxia (for example, compounds based on 2-nitroimidazole and compounds based on benzotriazine dioxide) that mimic oxygen or, alternatively, behave as bio-reducing agents during hypoxia; radiosensitizers that do not lead to cell hypoxia (for example, halogenated pyrimidines) can be analogs of DNA bases and are predominantly incorporated into the DNA of cancer cells and thus contribute to radiation-induced destruction of DNA molecules and / or interfere with normal DNA repair mechanisms; and various other possible mechanisms of action have been hypothesized for radiosensitizers in the treatment of disease.

Many cancer treatment protocols currently use radiosensitizers in conjunction with X-ray irradiation. Examples of X-ray-activated radiosensitizers include, but are not limited to, the following: metronidazole, mizonidazole, desmethylmisonidazole, pimonidazole, ethanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-hydroxy-bromide ( (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin and their therapeutically effective analogs and derivatives.

Photodynamic therapy (PDT) of cancers uses visible light as a radiation activator of a sensitizer. Examples of photodynamic radiosensitizers include, but are not limited to, the following: hematoporphyrin derivatives, photofrin, benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-α, bacteriochlorophyll-α, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and their therapeutically effective analogs and derivatives.

Radiosensitizers can be co-administered with a therapeutically effective amount of one or more other compounds, including, but not limited to, compounds that promote the incorporation of radiosensitizers into target cells; compounds that control the supply of therapeutic agents, nutrients and / or oxygen to target cells; chemotherapeutic agents that act on the tumor with or without additional radiation; or other therapeutically effective compounds for the treatment of cancer or other diseases.

Chemosensitizers can be co-administered with a therapeutically effective amount of one or more other compounds, including, but not limited to, compounds that allow the chemosensitizers to be incorporated into target cells; compounds that control the supply of therapeutic agents, nutrients and / or oxygen to target cells; chemotherapeutic agents that act on a tumor, or other therapeutically effective compounds for the treatment of cancer or other disease. It has been found that calcium antagonists such as verapamil are useful in combination with antineoplastic agents to render chemotherapy responsive to tumor cells resistant to standard chemotherapeutic agents and to enhance the efficacy of such compounds against drug-susceptible malignancies.

The present invention relates to compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for use as a medicament.

The present invention also relates to compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for use in inhibiting PI3Ke kinase activity and optionally also for use in inhibiting PI3Kδ.

The compounds of the present invention may be anti-cancer agents, the term also encompasses anti-tumor cell growth agents and anti-tumor agents.

The present invention also relates to compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for use in the treatment of the aforementioned diseases.

The present invention also relates to the compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for the treatment or prevention, in particular for the treatment of said diseases.

The present invention also relates to compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for the treatment or prevention, in particular for the treatment of PI3Ke-mediated diseases or conditions.

The present invention also relates to compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for the treatment or prevention, in particular for the treatment of PI3Ke and optionally PI3Kδ mediated diseases or conditions.

The present invention also relates to the use of compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for the manufacture of a medicament.

The present invention also relates to the use of compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for the preparation of a medicament for inhibiting PI3Ke.

The present invention also relates to the use of compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for the manufacture of a medicament for inhibiting PI3Ke and optionally also for inhibiting PI3Kδ.

The present invention also relates to the use of compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for the preparation of a medicament for the treatment or prevention, in particular for the treatment, of any of the disease states mentioned herein.

The present invention also relates to the use of compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates for the manufacture of a medicament for the treatment of any of the disease states mentioned herein.

The compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates can be administered to mammals, preferably humans, for the treatment or prevention of any of the diseases mentioned herein.

In view of the applicability of the compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, there is provided a method of treating warm-blooded animals, including humans, suffering from any of the diseases mentioned above, or a method of prevention in warm-blooded animals, including people, any of the diseases mentioned in this document.

These methods include administration, i. E. systemic or local administration, preferably oral administration, of an effective amount of a compound of formula (I) or its N-oxide, a pharmaceutically acceptable addition salt or solvate in warm-blooded animals, including humans.

Those skilled in the art of treating such diseases will be able to determine the effective therapeutic daily amount from the test results presented below in this document. An effective daily therapeutic amount will be from about 0.005 to 50 mg / kg, in particular from 0.01 to 50 mg / kg of body weight, more specifically from 0.01 to 25 mg / kg of body weight, preferably from about 0.01 to about 15 mg / kg, more preferably from about 0.01 to about 10 mg / kg, even more preferably from about 0.01 to about 1 mg / kg, most preferably from about 0.05 to about 1 mg / kg, weight body. The amount of a compound of the present invention, also referred to herein as an active ingredient, which is required to achieve a therapeutic effect will, of course, vary from case to case, for example, for a particular compound, route of administration, age and condition of the patient being treated, as well as the particular disorder or disease to be treated.

The method of treatment may also comprise administering the active ingredient on a schedule of one to four administrations per day. In these methods of treatment, the compounds of the present invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations are prepared using known procedures using well known and commonly available ingredients.

Compounds of the present invention that may be suitable for the treatment or prevention of cancer or cancer-related conditions can be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes the administration of a single dosage pharmaceutical composition that contains a compound of formula (I), its N-oxide, a pharmaceutically acceptable addition salt or solvate, and one or more additional therapeutic agents, as well as the administration of a compound of formula (I), its N-oxide, a pharmaceutically acceptable addition salt or solvate; and each of the additional therapeutic agents, each in a separate dosage pharmaceutical formulation. For example, a compound of formula (I), an N-oxide thereof, a pharmaceutically acceptable addition salt or solvate, and a therapeutic agent can be administered to a patient together in a single oral dosage composition such as a tablet or capsule, or each agent can be administered separately in dosage formulations for oral administration.

Although the active ingredient can be administered alone, it is preferred if it is presented in the form of a pharmaceutical composition.

Therefore, the present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound of formula (I), an N-oxide thereof, a pharmaceutically acceptable addition salt or solvate.

The carrier or diluent must be acceptable in the sense that it must be compatible with the other ingredients of the composition and not be harmful to the patients receiving it.

To facilitate administration, the compounds of the present invention can be formulated in various pharmaceutical forms for administration purposes. The compounds of the present invention, in particular the compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates, or any subgroup or combination thereof, can be formulated into various pharmaceutical forms for administration purposes. As suitable compositions there may be cited all compositions usually employed for systemically administered drugs.

To prepare pharmaceutical compositions according to the present invention, an effective amount of a specified compound as an active ingredient is intimately combined with a pharmaceutically acceptable carrier, the carrier taking a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unit dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation. For example, in the preparation of compositions in dosage form for oral administration, in the case of liquid preparations for oral administration such as suspensions, syrups, elixirs, emulsions and solutions, any of the usual pharmaceutical media can be used, for example water, glycols, oils, alcohols, etc. .P.; or solid carriers such as starch, sugar, kaolin, diluents, lubricants, binders, disintegrants, etc., in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules are the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. In the case of compositions for parenteral administration, the carrier will generally at least substantially comprise sterile water, although other ingredients, for example, to aid solubility, may be included. For example, injection solutions can be prepared in which the carrier contains saline, glucose solution, or a mixture of saline and glucose solution. Injection solutions containing a compound of formula (I), an N-oxide thereof, a pharmaceutically acceptable addition salt or solvate can be formulated in an oil for sustained release. Suitable oils for this purpose are, for example, nut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids, and mixtures of these and other oils. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be used. Also included are solid form preparations which are intended to be converted to liquid form preparations immediately prior to use. In compositions suitable for percutaneous administration, the carrier optionally includes a penetration enhancing agent and / or a suitable wetting agent, optionally in combination with suitable additives of any nature in minimal proportions, the additives not having a significant deleterious effect on the skin. These additives may facilitate transdermal administration and / or may be useful in obtaining the desired compositions. These compositions can be administered in various ways, for example, in the form of a transdermal patch, by spot application, in the form of an ointment. Acid or base addition salts of compounds of formula (I), due to their increased water solubility over the corresponding base or acid form, are more suitable in the preparation of aqueous compositions.

It is particularly preferred to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically separate units suitable as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including divisible or coated tablets), capsules, pills, powder sachets, plates, suppositories, injection solutions or suspensions, and the like, as well as separate sets thereof.

To increase the solubility and / or stability of the compounds of formula (I) and their N-oxides, pharmaceutically acceptable addition salts and solvates in pharmaceutical compositions, it may be preferable to use α-, β- or γ-cyclodextrins or their derivatives, in particular hydroxyalkyl-substituted cyclodextrins for example 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Co-solvents such as alcohols can also improve the solubility and / or stability of the compounds of the present invention in pharmaceutical compositions.

- 31 037871

Depending on the route of administration, the pharmaceutical composition will preferably contain from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of a compound of formula (I), its N-oxide, a pharmaceutically acceptable addition salt or solvate and from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages are based on the total weight of the composition.

As another aspect of the present invention, there is provided a combination of a compound of the present invention with another anticancer agent, especially for use as a medicament, more particularly for use in the treatment of cancer or related diseases.

For the treatment of the aforementioned conditions, the compounds of the present invention can advantageously be used in combination with one or more other medical agents, more particularly with other anti-cancer agents or adjuvants in cancer therapy. Examples of anti-cancer agents or adjuvants (therapy supportive agents) include, but are not limited to:

coordination compounds of platinum, for example cisplatin, optionally in combination with amifostine, carboplatin or oxaliplatin;

taxane compounds such as paclitaxel, protein-bound paclitaxel particles (Abraxane ™), or docetaxel;

topoisomerase I inhibitors such as camptothecin based compounds, eg irinotecan, SN-38, topotecan, topotecan HCl;

topoisomerase II inhibitors such as antineoplastic epidophyllotoxins or podophyllotoxin derivatives, for example etoposide, etoposide phosphate or teniposide;

antineoplastic vinca alkaloids such as vinblastine, vincristine or vinorelbine;

antineoplastic nucleoside derivatives, for example 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine;

alkylating agents such as nitrogen mustard or nitrosourea, for example cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide optionally in combination with proypomocyanine, strepolamide, strepolamide ;

antineoplastic anthracycline derivatives, for example daunorubicin, doxorubicin, optionally in combination with dexrazoxan, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin hcl, valrubicin;

molecules that target the IGF-1 receptor, such as picropodophilin; tetracarcin derivatives such as tetrocarcinoma A;

glucocorticoids such as prednisone;

antibodies such as trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, nofetumafetumab, CNTO

estrogen receptor antagonists or selective estrogen receptor modulators or estrogen synthesis inhibitors such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene, or letrozole;

aromatase inhibitors such as exemestane, anastrozole, letrazole, testolactone, and vorozol;

differentiating agents such as retinoids, vitamin D or retinoic acid, and retinoic acid metabolism blocking agents (RAMBA), such as accutane;

DNA methyltransferase inhibitors such as azacytidine or decitabine;

antifolates such as pemetrexed disodium;

antibiotics such as antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plikamycin, mithramycin;

antimetabolites such as clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacytidine, cytarabine, floxuridine, pentostatin, thioguanine;

apoptosis inducing agents and anti-angiogenic agents such as Bcl-2 inhibitors, for example YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;

tubulin binders such as combrestatin, colchicines, or nocodazole;

kinase inhibitors (eg, EGFR (Epidermal Growth Factor Receptor), MTKI (Multipurpose Kinase Inhibitors), mTOR inhibitors), eg flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, sapatinib, lapatinib, sootinibitol temsirolimus;

farnesyl transferase inhibitors such as tipifarnib;

histone deacetylase (HDAC) inhibitors such as sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A, vorinostat;

inhibitors of the ubiquitin-proteasome pathway, for example PS-341, MLN.41 or bortezomib;

- 32 037871 yondelis;

telomerase inhibitors such as telomestatin;

matrix metalloproteinase inhibitors such as batimastat, marimastat, prinostat, or metastat;

recombinant interleukins, for example aldesleukin, denileukin-diftitox, interferonalfa 2a, interferon-alpha 2b, peginterferon-alpha 2b;

MAPK inhibitors;

retinoids such as alitretinoin, bexarotene, tretinoin;

arsenic trioxide;

asparaginase;

steroids such as dromostanolone propionate, megestrol acetate, nandrolone (decanoate, fenpropionate), dexamethasone;

agonists or antagonists of gonadotropin-releasing hormone, for example abarelix, goserelin acetate, histrelin acetate, leuprolide acetate;

thalidomide, lenalidomide;

mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase, rasburicase;

BH3 mimetics such as ABT-737;

MEK inhibitors such as PD98059, AZD6244, CI-1040;

colony-stimulating factor analogs such as filgrastim, pegfilgrastim, sargramostim; erythropoietin or analogs thereof (eg darbepoetin alpha); interleukin-11;

oprelvekin; zoledronate, zoledronic acid; fentanyl; bisphosphonate; palifermin;

steroid inhibitor of cytochrome P450 17-alpha-hydroxylase / 17,20-lyase (CYP17), eg abiraterone, abiraterone acetate.

glycolysis inhibitors such as 2-deoxyglucose;

mTOR inhibitors such as rapamycins and rapalogs and mTOR kinase inhibitors;

PI3K inhibitors and dual mTOR / PI3K inhibitors;

autophagy inhibitors such as chloroquine and hydroxychloroquine;

antibodies that reactivate the immune response against tumors, such as nivolumab (anti-PD-1), lambrolizumab (anti-PD-1), ipilimumab (anti-CTLA4), and MPDL3280A (anti-PD-L1).

The compounds of the present invention can also advantageously be combined with antiandrogenic therapies, including androgen receptor antagonists and androgen biosynthesis inhibitors, in PTEN-negative prostate cancer.

The present invention also relates to a product containing, as a first active ingredient, a compound of the present invention and as an additional active ingredient, one or more anticancer agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

One or more other medical devices and a compound in accordance with the present invention can be administered simultaneously (eg, in separate or single compositions) or sequentially in a different order. In the latter case, two or more compounds will be administered over a period and in an amount and in a manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It should be borne in mind that the preferred mode and order of administration and the corresponding dose rates and regimens for each component of the combination will depend on the particular other medical agent and compound of the present invention to be administered, their route of administration, the particular tumor being treated, and the particular host. being treated. The optimal route and route of administration, as well as dosage amounts and regimen, can be easily determined by those skilled in the art using conventional methods and taking into account the information set forth herein.

The weight ratio of a compound of the present invention to one anti-cancer agent or several other anti-cancer agents administered in combination can be determined by one of ordinary skill in the art. The specified ratio, exact dosage and frequency of administration depend on the particular compound used according to the present invention and the other anticancer (anticancer) agent (s), the particular condition being treated, the severity of the condition being treated, age, body weight, sex, diet, the time of administration and the general physical condition of the particular patient, the route of administration, and other drug treatments that the individual may receive, as is well known to those of skill in the art. Moreover, it is obvious that the effective daily amount can be decreased or increased depending on the response of the subject being treated and / or depending on the judgment of the attending physician administering the compounds of the present invention. A specific weight ratio for a given compound of formula (I) and another anticancer agent may range from 1/10 to 10/1, more particularly from 1/5 to 5/1, even more particularly from 1/3 to 3 / one.

- 33 037871

The platinum coordination compound is preferably administered at a dose of 1-500 mg per square meter (mg / m ² ) of body surface area, for example 50-400 mg / m ² , in particular for cisplatin at a dose of about 75 mg / m ² and for carboplatin - at a dose of approximately 300 mg / m ² per course of treatment.

The taxane compound is advantageously administered at a dose of 50-400 mg per square meter (mg / m ² ) body surface area, for example 75-250 mg / m ² , in particular for paclitaxel at a dose of about 175-250 mg / m ² and for docetaxel - at a dose of approximately 75-150 mg / m ² per course of treatment.

The camptothecin compound is preferably administered at a dose of 0.1-0.1-400 mg per square meter (mg / m ² ) body surface area, for example 1-300 mg / m ² , in particular for irinotecan, at a dose of about 100 to 350 mg / m ² , and for topotecan, at a dose of about 1 to 2 mg / m ² per course of treatment.

The antitumor derivative of podophyllotoxin is preferably administered at a dose of 30-300 mg per square meter (mg / m ² ) of body surface area, for example 50-250 mg / m ² , in particular for etoposide at a dose of about 35-100 mg / m ² and for teniposide - at a dose of approximately 50-250 mg / m ² per course of treatment.

The antitumor vinca alkaloid is preferably administered at a dose of 2-30 mg per square meter (mg / m ² ) of body surface area, in particular for vinblastine at a dose of about 3 to 12 mg / m ² , for vincristine at a dose of from about 1 to 2 mg / m ² , and for vinorelbine at a dose of from about 10 to 30 mg / m ² per course of treatment.

An antitumor nucleoside derivative is preferably administered at a dose of 200-2500 mg per square meter (mg / m ² ) of body surface area, for example 700-1500 mg / m ² , in particular, for 5-FU, at a dose of 200 to 500 mg / m ² , for gemcitabine, at a dose of about 800 to 1200 mg / m ² , and for capecitabine, at a dose of about 1000 to 2500 mg / m ² , during the course of treatment.

Alkylating agents, such as nitrogen mustard gas or nitrosourea, are preferably administered at a dose of 100 to 500 mg per square meter (mg / m ² ) body surface area, for example 120 to 200 mg / m ² , in particular for cyclophosphamide - at a dose of about 100 to 500 mg / m ² , for chlorambucil at a dose of about 0.1 to 0.2 mg / kg, for carmustine at a dose of about 150 to 200 mg / m ² and for lomustine, at a dose of about 100 to 150 mg / m ² per course of treatment.

The antitumor anthracycline derivative is preferably administered at a dose of 10 to 75 mg per square meter (mg / m ² ) of body surface area, for example 15 to 60 mg / m ² , in particular for doxorubicin at a dose of about 40 up to 75 mg / m ² , for daunorubicin at a dose of about 25 to 45 mg / m ² and for idarubicin at a dose of about 10 to 15 mg / m ² during the course of treatment.

The antiestrogenic agent is advantageously administered at a dose of about 1 to 100 mg per day, depending on the particular agent and condition to be treated. Tamoxifen is preferably administered orally at a dose of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing therapy for a time sufficient to achieve and maintain a therapeutic effect. Toremifene is preferably administered orally at a dose of about 60 mg once a day, continuing therapy for a sufficient time to achieve and maintain a therapeutic effect. Anastrozole is preferably administered orally at a dose of about 1 mg once a day. Droloxifene is preferably administered orally at a dose of about 20 to 100 mg once a day. Raloxifene is preferably administered orally at a dose of about 60 mg once a day. Exemestane is preferably administered orally at a dose of about 25 mg once a day.

Antibodies are advantageously administered at a dose of about 1 to 5 mg per square meter (mg / m ² ) body surface area or, as is known in the art, at a different dose. Trastuzumab is advantageously administered at a dose of 1 to 5 mg / m ² body surface area, in particular 2 to 4 mg / m ² , per course of treatment.

These doses can be administered, for example, once, twice or more per course of treatment, which can be repeated, for example, every 7, 14, 21 or 28 days.

Examples of

The following examples illustrate the present invention.

If the stereocenter is designated RS, this means that a racemic mixture was obtained.

Hereinafter, the term ACN means acetonitrile, AcOH means acetic acid, aq. means aqueous, Ar means argon, BINAP means 2,2'-bis- (diphenylphosphino) -1,1'binaphthyl, BOC means t-butyloxycarbonyl, Boc ₂ O means di-t-butyldicarbonate, Celite® means diatomaceous earth, DavePhos means 2-dicyclohexylphosphino-2 '- (N, Ndimethylamino) biphenyl, DCM means dichloromethane, DIPE means diisopropyl ether, DIPEA means diisopropylethylamine, DMF means dimethylformamide, DPPP means 1,3-bis- (diphenylphosphino) propane, Et ₂ O means diethyl ether , EtOAc stands for ethyl acetate, EtOH stands for ethanol, h stands for hour (s), HPLC stands for high performance liquid

- 34 037871 chromatography, LC / MS means liquid chromatography / mass spectrometry, MeOH means methanol, min means minute (minutes), so pl. means melting point, MsCl means methanesulfonyl chloride, NaBH (OAc) ₃ means sodium triacetoxyborohydride, NaRi means Raney nickel, NMR means nuclear magnetic resonance, Pd (OAc) ₂ means palladium (P) acetate, quant. means quantitative, c.t. means room temperature, Rt means retention time, palladacycle RuPhos means chloropalladium, dicyclohexyl- [2- [2,6-di (propan-2-yloxy) phenyl] phenyl] phosphane, 2-methoxy-2-methylpropane, 2-phenylethanamine, saturate means saturated, SeO ₂ means selenium dioxide, TBAF means tetrabutylammonium fluoride, TBDMS or SMDBT means tert-butyldimethylsilyl, TEA 'means triethylamine, TFA means trifluoroacetic acid, THF means tetrahydrofuran, TLC means thin layer chromatography.

A. Obtaining intermediates.

Example A1.

Preparation of Intermediate 1

2-Methyl-3-chlorobenzylamine (1.33 g, 8.55 mmol) was added to a solution of 2,4-dichloro-5-nitropyridine (1.50 g, 7.77 mmol) and TEA (3.2 mL, 23 , 32 mmol) in THF (30 ml). The reaction mixture was stirred overnight at room temperature, diluted with DCM and washed with water. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was taken up with Et ₂ O and the precipitate was filtered and dried in vacuo to give 2 g of intermediate 1 (82% yield).

Preparation of Intermediate 2

A mixture of intermediate 1 (2.00 g, 6.41 mmol) in morpholine (15 ml) was heated at 100 ° C for 1 h. The reaction mixture was cooled to room temperature and CH3CN was added. The precipitate was filtered, washed with Et ₂ O and dried under vacuum to give a first batch of intermediate 2. The filtrate was evaporated to dryness and combined with the first batch. The residue was dissolved in DCM and washed with 10% K ₂ CO ₃ aqueous solution. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was taken up with CH ₃ CN and the precipitate was filtered, washed with Et ₂ O and dried to give 2.18 g of intermediate 2 (94% yield).

The intermediate below was prepared according to the same method as intermediate 2.

Preparation of Intermediate 3

A suspension of intermediate compound 2 (500.00 mg, 1.26 mmol) and RaNi (547.24 mg, 9.32 mmol) in MeOH (30 ml) was hydrogenated at room temperature in an atmosphere of H ₂ (1 atm) for 3 h The catalyst was removed by filtration through a Celite® pad and the filtrate was evaporated to dryness.

35,037871 states (azeotropic distillation with toluene to remove traces of water) to give 432 mg of intermediate 3 (94% yield), which was used directly in the next reaction step.

Example A2.

Preparation of Intermediate 4

2-Methyl-3- (trifluoromethyl) benzylamine (1.00 g, 5.29 mmol) was added to a solution of 2,4-dichloro-5nitropyridine (927.39 mg, 4.81 mmol) and TEA (2 ml, 14, 42 mmol) in THF (20 ml). The reaction mixture was stirred overnight at room temperature, diluted with DCM and washed with water. The organic layer was filtered through Chromabond® and evaporated to dryness. The residue was taken up with Et ₂ O and the precipitate was filtered and dried in vacuo to give 1.65 g of intermediate 4 (99% yield).

Preparation of Intermediate 5

A mixture of intermediate 4 (1.65 g, 4.77 mmol) in morpholine (10 ml) was heated at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature and DCM and water were added. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was taken up with CH3CN and the precipitate was filtered, washed with Et2O and dried in vacuo to give 1.6 g of intermediate 5 (85% yield).

Preparation of Intermediate 6

A suspension of intermediate compound 5 (1.12 g, 2.83 mmol) and RaNi (1.00 g, 17.04 mmol) in MeOH (70 ml) was hydrogenated at room temperature in an atmosphere of H ₂ (1 atm) for 3 h The catalyst was removed by filtration through a Celite pad and the filtrate was evaporated to dryness (azeotropic distillation with toluene to remove traces of water) to give 949 mg of intermediate 6 (92% yield) which was used directly in the next reaction step.

Example A3.

Preparation of Intermediate 11

4-Amino-2,6-dichloropyridine (40.00 g, 245.39 mmol) was slowly added to H ₂ SO ₄ (280 ml) at rt. and the reaction mixture was cooled to 5 ° C. _{HNO 3} (53.00 g, 841.10 mmol) was added and the reaction mixture was stirred at 10 ° C for 1 h. The reaction mixture was slowly poured into ice water and the precipitated solid was filtered and dried under vacuum to give 50 g of intermediate 11 (98% yield, light yellow solid).

Preparation of Intermediate 12

Sulfuric acid (32 ml) was placed in a 250 ml round bottom flask equipped with a magnetic stirrer and an internal thermometer. Intermediate 11 (6.19 g, 29.7 mmol) was added in portions (internal temperature should remain below 40 ° C). The mixture was heated to 100 ° C for 1 h, poured into ice water (300 ml) and the pH of the solution was adjusted to 9.5 by adding 6N HCl. aq. NaOH solution (250 ml). The suspension was stirred for 30 min at rt. The precipitate was collected 36,037871 by filtration, suspended in water (150 ml) and stirred at rt. within 30 minutes. The solid was collected by filtration and dried under high vacuum overnight to provide 5.47 g of intermediate 12 (88% yield, off-white solid).

Preparation of Intermediate Compound 13

To a solution of intermediate 12 (37.00 g, 177.88 mmol) in HCl (60 ml) and EtOH / H2O solution (400 ml, 1: 1, v / v) was added iron powder (30.00 g, 537.20 mmol). The reaction mixture was stirred at 100 ° C for 3 hours. The reaction mixture was concentrated and diluted with water. The basicity of the suspended solution was increased with an aqueous solution of NaHCO ₃ to pH 9. The precipitate was filtered and diluted in a mixture of EtOAc / MeOH (8: 1, v / v). The remaining solid was filtered and the filtrate was concentrated in vacuo to provide a first batch of intermediate 13.

The main filtrate was extracted with EtOAc (3 times) and the combined organic layers were concentrated in vacuo to give a second batch of intermediate 13.

The two batches were combined and the resulting solid was triturated with ether, filtered and dried in vacuo to give 30 g of intermediate 13 (95% yield, light yellow solid).

The intermediate shown in the table below was obtained by applying a method similar to that described for the preparation of intermediate 13, starting from the appropriate starting materials.

Preparation of Intermediate 14

To a solution of intermediate 13 (16.00 g, 89.88 mmol) in EtOH (60 ml) was added triethoxyethane (50 ml) and conc. HCl (4 ml) and the mixture was stirred at 100 ° C for 16 hours. The mixture was concentrated and diluted with water and ethyl acetate. The layers were separated and the organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (mobile phase gradient: 100% petroleum ether, 0% EtOAc to 0% petroleum ether, 100% EtOAc). The product containing the fractions was collected and the solvent was evaporated, yielding 11 g of intermediate 14 (57% yield, yellow solid).

The intermediate shown in the table below was obtained by applying a method similar to that described for the preparation of intermediate 14, starting from the appropriate starting materials.

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Preparation of Intermediate 15

2-Methyl-3- (trifluoromethyl) benzyl bromide (6.26 g, 24.7 mmol) was added to a mixture of intermediate 14 (5.00 g, 24.7 mmol) and K ₂ CO ₃ (6.84 g, 49 , 5 mmol) in CH3CN (500 ml). The reaction mixture was stirred for 2 h at 85 ° C. Water and EtOAc were added to the mixture. The layers were separated and the organic layer was washed with water (twice), brine and water. The organic layer was dried over MgSO ₄ , filtered and evaporated to dryness. The residue was taken up with DIPE to give 9.23 g of intermediate 15 (quant. Yield).

Example A4.

Preparation of Intermediate 7

A mixture of compound 2 (1.00 g, 2.56 mmol) and SeO ₂ (426.00 mg, 3.84 mmol) in 1,4-dioxane (15 ml) was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with DCM and added 10% aqueous K ₂ CO ₃ solution. The organic layer was recovered, filtered through Chromabond® and evaporated to dryness to give 1.04 g of intermediate 7 (quant. Yield), which was used in the next step without further purification.

The intermediate shown in the table below was obtained by applying a method similar to that described for the preparation of intermediate 7, starting from the appropriate starting materials.

Example A5.

Preparation of Intermediate 8

Benzoyl chloride (0.56 ml, 4.78 mmol) was added to a solution of 2-boc-6-hydroxy-2-azaspiro [3.3] heptane (850.00 mg, 3.99 mmol) and TEA (0.77 ml , 5.58 mmol) in DCM (17 ml) at room temperature. The reaction mixture was stirred overnight at room temperature, diluted with DCM and washed with 10% aqueous K ₂ CO ₃ solution. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (irregular grain SiOH, 24 g, mobile phase gradient: 0% MeOH, 100% DCM to 3% MeOH, 97% DCM). The pure fractions were collected and evaporated to dryness to give 1.08 g of intermediate 8 (85% yield).

Preparation of Intermediate 9

TFA was added dropwise (5 ml, 65.34 mmol) to a solution of intermediate 8 (1.08 g, 3.40 mmol) in DCM (50 ml) at 0 ° C and the reaction mixture was stirred at room temperature for 2 h A 10% aqueous K ₂ CO ₃ solution was added and the organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness to give 739 mg of intermediate 9, which was used in the next step without further purification.

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Preparation of Intermediate 10

A mixture of intermediate 7 (260.00 mg, 0.64 mmol) and intermediate 9 (279.38 mg, 1.29 mmol) in DCM (6 ml) was stirred at room temperature for 18 h. Sodium triacetoxyborohydride (272 , 53 mg, 1.29 mmol) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with DCM and poured into a 10% aqueous K2CO3 solution. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (irregular grain SiOH, 24 g, mobile phase gradient: 3% MeOH, 97% DCM to 5% MeOH, 95% DCM). The product containing the fractions was collected and evaporated to dryness to give 250 mg of intermediate 10 (64% yield).

The intermediate shown in the table below was obtained by applying a method similar to that described for the preparation of intermediate 10, starting from the appropriate starting materials.

Example A6.

Preparation of Intermediate 16

In a sealed tube, a mixture of intermediate 15 (1.70 g, 4.54 mmol), benzhydrylideneamine (1.14 ml, 6.82 mmol) and Cs ₂ CO ₃ (4.44 g, 13.63 mmol) in 1, 4-dioxane (50 ml) was degassed with N2. BINAP (141.00 mg, 0.23 mmol) and Pd (OAc) 2 (51.00 mg, 0.23 mmol) were added. The reaction mixture was heated at 100 ° C for 48 h. The reaction mixture was cooled to room temperature, water and EtOAc were added and the mixture was filtered through a pad of celite. The organic layer was decanted, washed with water and brine, dried over MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified by preparative LC (stationary phase: irregular grain SiOH, 40 μm, 120 g, mobile phase gradient: 90% heptane, 10% EtOAc to 60% heptane, 40% EtOAc) to give 779 mg of intermediate 16 (with a yield of 33%).

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Preparation of Intermediate 37

The experiment was repeated 9 times using 50 mg of intermediate 16.

Morpholine (10.17 μl, 0.12 mmol) was added to a solution of intermediate 16 (50.00 mg, 0.096 mmol) and Cs ₂ CO ₃ (94.17 mg, 0.29 mmol) in 1,4-dioxane ( 1 ml). The solution was degassed with N ₂ and Pd (OAc) ₂ (1/1 mg, 0.0 05 mmol) and DavePhos (1.90 mg, 0.005 mmol) was added. The reaction mixture was heated at 120 ° C for 24 h. Water and EtOAc were added and the reaction mixture was filtered through a celite pad. The organic layer was extracted, washed with water and brine, dried over MgSO ₄ , filtered and evaporated to dryness. Nine reaction products were combined and the resulting crude residue was purified by preparative LC (stationary phase: SiOH with irregular grains, 15-40 μm, 80 g MERCK, mobile phase gradient: 80% heptane, 20% EtOAc to 40% heptane, 60% EtOAc) to give 200 mg of intermediate 37 (40% yield).

Example A7.

Preparation of Intermediate 17

To a solution of intermediate 16 (250.00 mg, 0.48 mmol) in H ₂ O (730 μl) and 1,4-dioxane (37.5 ml) was added 2- (3,6-dihydro-2H-pyran- 4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (303.60 mg, 1.4 5 mmol) and K ₃ PO ₄ (306.76 mg, 1.45 mmol) ... The reaction mixture was degassed with N ₂ and palladacycle RuPhos (9.84 mg, 0.012 mmol) was added to the mixture. The reaction mixture was heated at 105 ° C overnight. Water and EtOAc were added and the mixture was filtered through a celite pad. The organic layer was decanted, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. Purification was performed by preparative LC (stationary phase: irregularly shaped SiOH, 40 μm, 40 g, mobile phase gradient: 100% DCM, 0% MeOH to 97% DCM, 3% MeOH) to give 125 mg of intermediate 17 ( with a yield of 46%).

The intermediate shown in the table below was obtained by applying a method similar to that described for the preparation of intermediate 17, starting from the appropriate starting materials.

Intermediate number Structure Intermediate 35 (from Intermediate 4) o XX ^h ° ^_ F ^ FF

- 40 037871

Example A8.

Preparation of Intermediate 36

Iron powder (198.05 mg, 1.18 mmol) and AcOH (1.35 ml, 23.64 mmol) were added to a solution of intermediate 35 (465.00 mg, 1.18 mmol) in MeOH (6.2 ml ) at c.t. The reaction mixture was heated at 80 ° C overnight. Water and EtOAc were added and the mixture was filtered through a Celite® pad. The organic layer was extracted, washed with water and brine, dried over MgSO ₄ , filtered and evaporated to give 289 mg of intermediate 36 (61% yield).

Example A9.

Preparation of Intermediate 19

TBDMS

TBDMSCl (3.30 g, 21.91 mmol) was added to a solution of azetidin-3-ol (2.00 g, 18.26 mmol) and TEA (7.61 ml, 54.77 mmol) in DCM (60 ml) at room temperature. The reaction mixture was stirred overnight at room temperature and washed with aqueous saturated Na ₂ CO ₃ (100 ml).

The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (irregular grain SiOH, 40 g, mobile phase gradient: 0.5% NH4OH, 5% MeOH, 95% DCM to 1.5% NH4OH, 15% MeOH, 85% DCM) ... The product containing the fractions was collected and evaporated to dryness to give 2.9 g of intermediate 19 (85% yield).

Example A10.

Preparation of Intermediate 21

Bg

NaBH3CN (30.20 g, 480.64 mmol) was added to a mixture of 8-bromisoquinoline (20.00 g, 96.13 mmol) in MeOH (300 ml) at 0 ° C. The resulting mixture was stirred for 10 min and boron trifluoride diethyl etherate (68.22 g, 480.64 mmol) was added dropwise at 0 ° C. The resulting mixture was stirred for 1 h at 0 ° C and then heated under reflux for 4 h. Sat. Na ₂ CO ₃ (5 ml) and the solvent was concentrated under reduced pressure. The remaining liquid was poured into water and extracted with CH ₂ Cl ₂ . The organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo to give 20 g of intermediate 21 (98% yield) which was used in the next step without further purification.

Preparation of Intermediate 22

_{Boc 2} O (25.73 g, 117.88 mmol) was added dropwise to a solution of intermediate 21 (25.00 g, 117.88 mmol) and TEA (32.83 mL, 236.00 mmol) in DCM (300 ml) at 0 ° C. The resulting mixture was stirred at room temperature for 30 minutes. To quench the reaction, sat. citric acid and the layers were separated. The organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude residue was purified using a silica gel column (mobile phase: petroleum ether / EtOAc, 3/1, v / v) to give 35 g of intermediate 22 (95% yield).

Preparation of Intermediate Compound 24

1,2,3,4-Tetrahydroisoquinoline-8-carboxylic acid (2.13 g, 9.97 mmol) was dissolved in a 50% aqueous solution of 1,4-dioxane (25 ml) and Na ₂ CO ₃ (2.11 g, 19.94 mmol) followed by the addition of

- 41 037871

Boc ₂ O (2.61 g, 11.96 mmol). The mixture was stirred at rt. Boc ₂ 0 (500.00 mg,

2.30 mmol) and the reaction mixture was stirred for 1 day. The reaction mixture was concentrated and water (20 ml) was added. The solution was acidified to pH 2 by adding 2 M HCl. The resulting solid was collected by filtration and dried overnight to provide 2.65 g of intermediate 24 (96% yield).

Preparation of Intermediate Compound 23

Pd (OAc) 2 (1/58 g, 7.05 mmol) was added to a mixture of intermediate 22 (22.00 g, 70.47 mmol), DPPP (2.91 g, 7.05 mmol) and TEA (49 , 11 ml, 352.34 mmol) in MeOH / DMF solution (300 ml, 2: 1, v / v). The resulting solution was stirred and supplied with CO at a pressure of 40 psi. at 70 ° C for 4 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (mobile phase gradient: 91% petroleum ether, 9% EtOAc to 83% petroleum ether, 17% EtOAc) to give 12 g of intermediate 23 (59% yield).

Preparation of Intermediate 25

LiAlH ₄ (493.00 mg, 13.00 mmol) was added portionwise to a solution of intermediate 23 (5.00 g, 12.01 mmol) in THF (100 ml) at 0 ° C. The mixture was stirred at 0 ° C for 1 h. To quench the reaction, H ₂ O (500 μl) and 2N. aqueous NaOH solution (500 μl). The mixture was filtered through celite and washed with THF. The filtrate was evaporated and the crude residue was purified by column (mobile phase gradient: 91% petroleum ether, 9% EtOAc to 80% petroleum ether, 20% EtOAc) to give 3.1 g of intermediate 25 (97% yield).

Alternative preparation of intermediate 25

To a solution of intermediate 24 (500.00 mg, 1.80 mmol) in THF (18 ml) at 0 ° C was added BH3.THF complex (1 M in THF) (1.80 ml, 1.80 mmol). The solution was allowed to warm to rt and then heated at 40 ° C for 2 h. The mixture was then cooled to 0 ° C and BH3.THF (1.80 ml, 1.80 mmol) was added. The solution was allowed to warm to rt and then heated at 50 ° C for 18 hours. The crude product was then cooled to 0 ° C and BH3.THF (5.41 mL, 5.41 mmol) was added. Allow the solution to warm to rt, and then heated under reflux for 18 h. The mixture was cooled to 0 ° C and carefully added 3N. aqueous HCl solution. The mixture was stirred at rt. for 1 h and was extracted with EtOAc (three times). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude residue was purified by preparative LC (irregular grain SiOH, 15-40 μm, 30 g Merck, mobile phase gradient DCM 100% to DCM 95%, MeOH 5%) to give 449 mg of intermediate 25 (95 %, colorless oil).

Preparation of Intermediate 26

Add MsCl (5.22 g, 45.6 mmol) to a solution of intermediate 25 (10.00 g, 37.98 mmol) and TEA (10.59 ml, 76 mmol) in DCM (100 ml) at 0 ° C ... The resulting solution was stirred at 0 ° C for 2 hours. The resulting mixture was poured into water and extracted with CH ₂ Cl ₂ (3x100 ml). The organic layer was washed with sat. NaHCO ₃ solution and brine, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give 12.97 g of intermediate 26 (quant. yield) which was used in the next step without further purification.

Preparation of Intermediate Compound 27

A mixture of intermediate 26 (12.96 g, 37.96 mmol) and the potassium salt of phthalimide (10.55 g, 56.96 mmol) in 1,4-dioxane (150 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was poured into water and extracted with EtOAc (3x100 ml). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The crude residue was purified using a silica gel column (mobile phase gradient: 83% petroleum ether, 17% EtOAc to 75% petroleum ether, 25% EtOAc) to give 6 g of intermediate 27 (40% yield, white solid).

Preparation of Intermediate 28

Hydrazine monohydrate (1.21 g, 22.93 mmol, 95% purity based on LC / MS data) was added to a solution of intermediate 27 (6.00 g, 15.29 mmol) in EtOH (100 mL) at c.t. The resulting mixture was heated under reflux for 3 hours. The solvent was evaporated in vacuo and the crude residue was purified by column (eluent: 100% EtOAc) to give 3.5 g of intermediate 28 (92% yield).

Preparation of Intermediate 29

A mixture of intermediate 12 (579.00 mg, 3.00 mmol), intermediate 28 (866.00 mg, 3.3 0 mmol) and TEA (1.25 ml, 9 mmol) in THF (20 ml) was stirred at room temperature for 3 h. Water was added and the product was extracted with EtOAc. The layers were separated and the organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The crude residue was washed with petroleum ether and dried in vacuo to give 1 g of intermediate 29 (75% yield, 95% purity based on LC / MS data).

Example A11.

Preparation of Intermediate 33

In a round bottom flask TBDMSCl (10.61 g, 70.42 mmol) and imidazole (6.23 g, 91.55 mmol) were dissolved in DMF (12.5 mL) and the solution was stirred for 30 min at RT. Then 2-bromoethanol (5 ml, 70.42 mmol) was added and the mixture was stirred at rt. over 16 h. The reaction mixture was partitioned between Et ₂ O and water. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo to give 17 g of intermediate 33 (quant. Yield, colorless oil).

Preparation of Intermediate 34

A mixture of compound 9а (200.00 mg, 0.4 9 mmol), intermediate compound 33 (351.66 mg, 1.47 mmol) and DIPEA (316.65 mg, 2.45 mmol) in ACN (10 ml) was stirred at c.t. over 14 hours. The solvent was removed under reduced pressure to give 339 mg of intermediate 34 (quant. yield, 75% purity based on LC / MS data) which was used in the next step without

- 43 037871 additional cleaning.

B. Preparation of Compounds.

Example B1.

Getting connection 1

CI

A mixture of intermediate 3 (432.00 mg, 1.30 mmol) and acetaldehyde (87.63 μl, 1.56 mmol) in 1-butanol (10 ml) was heated under reflux overnight. Acetaldehyde (175.26 μl, 3.12 mmol) was added and the mixture was heated under reflux for an additional 6 h, then stirred at rt. over 13 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (irregular grain SiOH, 30 g, mobile phase gradient: 0.3% NH4OH, 97% DCM, 3% MeOH to 0.6% NH4OH, 6% DCM, 94% MeOH). The product containing the fractions was collected and evaporated to dryness. The residue was then crystallized from Et2O, filtered and the solid was purified by reverse phase chromatography (X-Bridge-C18, 5 μm, 30x150 mm, mobile phase gradient: from 75% aq. NH4HCO ₃ (0.5%), 25% ACN up to 0% aq. NH4HCO ₃ (0.5%), 100% ACN). The pure fractions were collected and evaporated to dryness to give 50 mg of compound 1 (11% yield).

Getting connection 2

A mixture of intermediate 6 (451.00 mg, 1.23 mmol) and acetaldehyde (83.11 μl, 1.48 mmol) in 1-butanol (10 ml) was heated under reflux overnight. The solution was cooled to rt. and acetaldehyde (166.22 μl, 2.95 mmol) was added, the mixture was heated under reflux for an additional 6 h, then stirred at rt. over 13 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (irregular grain SiOH, 30 g, mobile phase gradient: 0.3% NH4OH, 97% DCM, 3% MeOH to 0.6% NH4OH, 6% DCM, 94% MeOH). The pure fractions were collected and evaporated to give 190 mg of compound 2 (39% yield).

The compound shown in the table below was obtained by applying a method similar to that described for the preparation of compound 2, starting from the appropriate starting materials.

Example B2.

Getting a connection 3 he

A mixture of intermediate 10 (234.00 mg, 0.39 mmol) and LiOH (64.85 mg, 1.55 mmol) in MeOH (5.6 ml) was stirred at room temperature overnight. The reaction mixture was diluted with DCM and water was added. The mixture was extracted with DCM (six times). United

- 44 037871 ny organic layers were dried over MgSO4, filtered and the solvent was evaporated to dryness. The crude residue was purified by chromatography on silica gel (stationary phase: unmodified silica with spherical grains 5 μm, 150x30.0 mm, mobile phase gradient: 0.3% NH4OH, 97% DCM, 3% MeOH to 1.5% NH4OH , 85% DCM, 15% MeOH). The pure fractions were collected and the solvent was evaporated to dryness to give a colorless oil which was taken up with DCM and pentane. The solvent was evaporated in vacuo to give 92 mg of compound 3 (47% yield, pale yellow foam).

Example B3.

Getting compound 4

HCl (1 Mb H ₂ O) (2.12 ml, 2.12 mmol) was added to a solution of intermediate 17 (120.00 mg, 0.21 mmol) in THF (5 ml). The reaction mixture was stirred at room temperature for 1 hour. An aqueous solution of K ₂ CO ₃ (10%) was added to the mixture until basic pH was reached. Added EtOAc and the organic layer was extracted, washed with water, filtered and concentrated under reduced pressure. The crude residue was crystallized from CH3CN and the precipitate was filtered, washed with Et ₂ O, and dried in vacuo to give 25 mg of compound 4 (35% yield).

The compounds shown in the table below were prepared by applying a method similar to that described for the preparation of compound 4, starting from the appropriate starting materials.

Connection number Structure Compound 12 nh ₂ fry- Compound 14 about-. Η ¹ Compound 15 (from Intermediate 37) about Compound 16 about Compound 17 about

- 45 037871

Example B4.

Getting compound 5

A mixture of intermediate 18 (176.52 mg, 0.48 mmol) and thiomorpholine-1,1-dioxide (96.52 mg, 0.71 mmol) in DCM (6 ml) was stirred overnight at room temperature. Sodium triacetoxyborohydride (201.77 mg, 0.95 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM and poured into a 10% aqueous K2CO3 solution. The organic layer was decanted, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (unmodified irregularly shaped silica, 150 g, mobile phase gradient: 98% DCM, 2% MeOH (+ 10% NH4OH) to 87% DCM, 13% MeOH (+ 10% NH4OH) ). The purified fractions were collected and evaporated to dryness. The residue was further purified by reverse phase chromatography (X-Bridge-C18, 5 μm, 30x150 mm, mobile phase gradient: 75% aq NH4HCO3 (0.5%), 25% ACN to 35% aq NH4HCO3 (0, 5%), 65% ACN). The pure fractions were collected and evaporated to dryness to give 49 mg of compound 5 (21% yield).

The compound shown in the table below was obtained by applying a method similar to that described for the preparation of compound 5, starting from the appropriate starting materials.

Example B5.

Getting compound 6

NaBH ₄ (28.07 mg, 0.74 mmol) was added in portions at 5 ° C to a solution of intermediate 7 (250.00 mg, 0.62 mmol) in MeOH (5 ml). The reaction mixture was stirred at room temperature for 3 hours, quenched with water and extracted with DCM. The organic layer was decanted, filtered through Chromabond® and evaporated to dryness. The residue was crystallized from CH3CN and the precipitate was filtered, washed with Et ₂ O and dried in vacuo to give 229 mg of compound 6 (91% yield).

Example B6.

Getting compound 7

TBAF (1 M in THF) (955.00 μl, 0.96 mmol) was added at 5 ° C to a solution of intermediate 20 (275.00 mg, 0.48 mmol) in 1,4-dioxane (5 ml). The reaction mixture was stirred at room temperature for 4 h, diluted with DCM and poured into a 10% aqueous K ₂ CO ₃ solution. The organic layer was decanted, dried over MgSO ₄ , filtered and concentrated to precipitation.

- 46 037871

The precipitate was filtered, washed with CH ₃ CN and Et2O and dried in vacuo to give

130 mg of compound 7 (with a yield of 59%).

Getting connection 11

but

Mixture of Intermediate 34 (339.00 mg, 0.49 mmol, 75% purity based on LC / MS data) and TBAF (1 M in THF) (2.45 mL, 2.45 mmol) in THF (10 ml) was stirred at rt. during the night. The reaction mixture was poured into water (50 ml) and diluted with EtOAc (100 ml). The aqueous layer was extracted with EtOAc (twice) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated to dryness. The crude product was purified by high performance liquid chromatography (column: Phenomenex Gemini 150x25 mmx10 μm, flow rate: 25 ml / min, mobile phase gradient: 85% water (containing 0.05% ammonia), 15% CH3CN to 55% water (containing 0 , 05% ammonia), 45% CH3CN, 0 to 10 min). The product containing the fractions was concentrated in vacuo to give 53 mg of compound 11 (30% yield).

Example B7.

Obtaining compound 9а

and compounds 9b (1.HCl):

A mixture of intermediate 32 (800.00 mg, 1.73 mmol) in TFA / DCM solution (10 ml, 1: 3, v / v) was stirred at room temperature for 5 hours. The solvent was removed and the residue was poured into water and adjusted the pH (pH> 7). The product was extracted with DCM and the organic layer was collected, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give compound 9a (450 mg; 64%, based on LC / MS, 89% purity). 150 mg of compound 9a was purified by HPLC (column: Gemini 150x25 mm, 5 μm, flow rate: 25 ml / min, mobile phase gradient: from 100% water (containing 0.1% HCl), 0% CH ₃ CN to 75% water, 25% CH3CN, from 0 to 16 min). The product containing the fractions was collected and the solvent was concentrated in vacuo to give 68 mg of compound 9b (1.HCl) (46% yield).

Example B8.

Getting connection 10

A mixture of compound 9а (163.35 mg, 0.40 mmol) and paraformaldehyde (1.80 g, 20.00 mmol) in MeOH (20 ml) was stirred at room temperature for 1 h. NaBH (OAc) ₃ (4 , 24 g, 20 mmol) and the resulting mixture was stirred for an additional 24 h. The mixture was filtered and the filtrate was evaporated in vacuo. The crude product was dissolved in ethyl acetate and the mixture was washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by high performance liquid chromatography (column: Gemini 150x25 mm, 5 μm, flow rate: 25 ml / min, mobile phase gradient: 100% water (containing 0.1% HCl), 0% CH ₃ CN to 75% water , 25% CH3CN, 0-16 min.). The product containing the fractions was collected and the solvent was concentrated in vacuo to give 96 mg of compound 10 (1.HCl) (57% yield).

C. Analytical part.

LCMS (liquid chromatography / mass spectrometry).

High performance liquid chromatography (HPLC) measurements were performed with an LC pump, diode array (DAD) or UV detector and column as described in the respective methods. If necessary, additional detectors were turned on (see the given

- 47 037871 below the table of methods).

The column stream was directed to a mass spectrometer (MS), which was equipped with an atmospheric pressure ionization source. It is within the competence of the person skilled in the art to set tunable parameters (eg, scan range, exposure time, etc.) in order to obtain ions that provide the determination of the nominal monoisotopic molecular weight (MW) of the compound. Data collection was performed using the appropriate software.

Compounds are described for their experimental retention times (Rt) and ions. Unless otherwise indicated in the datasheet, the indicated molecular ion corresponds to [M + H] + (protonated molecule) and / or [MH] ^- (deprotonated molecule). In case the compound was not directly ionizable, the type of adduct is indicated (ie [M + NH4] ⁺ , [M + HCOO] ^- , etc.). For molecules with complex isotopic distributions (Br, Cl, ...), the reported value is the value that was obtained for the lowest isotope mass.

All results were obtained with experimental uncertainties that are usually associated with the method used.

Hereinafter in this document, SQD stands for single quadrupole detector, ct. room temperature, VEN bridging ethylsiloxane / silica hybrid, high strength HSS silica, DAD detector on a diode array, MSD mass selective detector.

LCMS method codes (flow expressed in ml / min;

column temperature (T) in ° C; analysis time in minutes)

Way code Appliance Column Mobile phase Gradient Consumption (ml / min.) Analysis time for T (° C) one Waters: Acquity UPLC® - DAD and Quattro Micro ™ Waters: VEN C18 (1.7 μm, 2.1x100 mm) A: 95% 7 mM CH3COONH4 / 5% CH ₃ CN, B: CH ₃ CN From 84.2% A for 0.49 min. up to 10.5% A in 2.18 min. , retention for 1.94 min., back to 84.2% A in 0.73 min., retention for 0.73 min. 0.343 6.2 40 2 Agilent 1200, MSD 6110 Agilent TC-C18 (5 MKM, 2,1x50 mm) A: water (+ 0.1% TFA), B: CH ₃ CN (+ 0.1% TFA) From 100% A for 1 min. up to 40% A in 4 minutes, up to 15% A in 2.5 minutes, back to 100% A in 2 minutes, holding for 0.5 minutes. 0.8 10 fifty 3 Agilent 1200, MSD 6110 XBridge Shield RP18 (5 μm, 2.1x50 mm) A: water (+ 0.05% NH ₃ .H ₂ O), B: CH ₃ CN From 100% A for 1 min. up to 40% A in 4 minutes, up to 5% A in 2.5 minutes, back to 100% A in 2 minutes, holding for 0.5 minutes. 0.8 40 10

Melting point (DSC or K).

For a number of compounds, the melting point (MP) values were determined using DSC1

- 48 037871 (Mettler-Toledo). Melting points were measured at a temperature gradient of 10 ° C / min. The maximum temperature was 350 ° C. Values represent peak values.

For a number of compounds, melting points were obtained using a Kofler stage (K) consisting of a heated plate with a linear temperature gradient, a sliding pointer and a temperature scale in degrees Celsius.

In the table, No. means compound number, MP means melting point (° C), R _t means retention time (min)

No. Compound MP (° C) Kofler (K) or DSC Rt [M + H] ⁺ Way LC / MS one хХ> ° 9 ^Νν -η 'Cl 177 TO 2, 62 357 one 2 about 136 TO 2.70 391 one 3 he] Ti l? F ^Z ' ^F 78 TO 2.51 502 one four nh ₂ ίτν F 225 DSC 2.73 403 one five About MV Ml'o about 238 TO 2.47 490 one

- 49 037871

- 50 037871

NMR.

NMR experiments were performed using a Bruker Avance 500 III with internal deuterium stabilization and a triple resonance probe with reverse detection (1H, ¹³ C, ¹⁵ N TXI). Chemical shifts (δ) are reported in parts per million (ppm). J values are expressed in hertz.

- 51 037871

Compound 1: 1H NMR (500 MHz, DMSO-d6): δ ppm 8.47 (s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.08 (t,

J = 7.9 Hz, 1H), 6.80 (s, 1H), 6.08 (d, J = 7.9 Hz, 1H), 5.45 (s, 2H), 3.65-3, 72 (m, 4H), 3.33-3.36 (m, 4H, partially obscured by the solvent peak), 2.45 (s, 3H), 2.35 (s, 3H).

Compound 3: 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.53 (s, 1H), 7.58 (d J = 7.9 Hz, 1H), 7.24 (t, J = 7, 7 Hz, 1H), 6.77 (s, 1H), 6.40 (d, J = 7.9 Hz, 1H), 5.53 (s, 2H), 4.87 (d, J = 6, 3 Hz, 1H), 3.77-3.85 (m, 1H), 3.66-3.70 (m, 4H), 3.65 (s, 2H), 3.34-3.36 (m , 4H, partially darkened by the solvent peak), 2.96-3.06 (m, 4H), 2.48-2.49 (m, 3H, partially darkened by the solvent peak), 2.03-2.13 (m, 2H), 1.61-1.73 (m, 2H).

Compound 4: 1H NMR (500 MHz, DMSO-d6): δ ppm 7.61 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 6, 78 (s, 1H), 6.56-6.60 (m, 1H), 6.39 (d, J = 7.9 Hz, 1H), 6.06 (s, 2H), 5.51 (s , 2H), 4.18-4.22 (m, 2H), 3.75 (t, J = 5.4 Hz, 2H), 2.51 (s, 3H, partially darkened by the solvent peak), 2.38 -2.43 (m, 2H), 2.36 (s, 3H).

Pharmacology.

Enzyme binding assays (KINOMEscan®).

The binding affinity of the compounds disclosed herein for kinase enzymes was determined using the KINOMEscan technology developed by DiscoveRx Corporation, San Diego, California, USA (www.kinomescan.com). Table A shows the resulting Kd values (nM), wherein Kd is the binding inhibition constant (n / a means not determined).

Table A

Conn. No. Kd PIK3Ca_h (μM) Kd PIK3Cp_h (μM) Kd PIK3C5_h (mkM) Kd PIK3Cy_h (mkM) Kd MTOR_h (mkM) 2 3.7 0, 002 1.5 22.4 > 30.2 one 2.1 0, 002 0, 6 9, 5 30.2 five 2, 6 0, 004 1.5 > 30.2 > 30.2 6 2.8 0, 001 0, 8 18.2 30.2 7 2.2 0, 003 1.1 > 30.2 4, 6 eight 11, 0 0.011 2, 6 > 30.2 > 30.2 3 sixteen 0, 001 0.2 > 30.2 > 30.2 nine > 30.2 0.079 5, 1 > 30.2 > 30.2 10 26, 9 0, 100 4.2 > 30.2 > 30.2 eleven θ, 7 0.027 1,3 32.4 > 30.2 four 17.0 0, 009 4.3 > 30.2 > 30.2 12 13.2 0, 003 0.7 > 30.2 > 30.2 13 5, 9 0, 003 1,3 17, 0 > 30.2 fourteen > 30.2 0.011 3.3 21, 9 > 30.2 sixteen > 30.2 0, 132 5, 6 > 30.2 > 30.2 fifteen 18.2 0.398 6, 3 > 30.2 > 30.2 17 8.3 0.019 1.5 > 30.2 > 30.2

Cellular analyzes.

The activity of PI3Ke inhibitors in cells was determined by quantitative assessment of Akt phosphorylation in PC-3 cells. The amount of Akt phosphorylated at Ser473 and Thr308 was measured using an enzyme-linked immunosorbent assay (ELISA; Meso Scale Discovery (MSD), Gaithersburg, MD) and specific primary antibodies from MSD.

On day 1, PC3 cells (ATCC # CRL-14351) were seeded in MW96 PerkinElmer plates at a density of 25,000 cells / well in 75 μl of complete culture medium (high glucose DMEM, AQmedia ™, D0819, Sigma-Aldrich) containing 10% thermally inactivated FCS and incubated at 37 ° C, 5% CO ₂ for 24 h. On day 2, compound or DMSO (0.3%) was added and the cells were further incubated for 60 min at 37 ° C, 5% CO ₂ in medium with a total volume of 100 μl.

Phosphoprotein analysis was performed according to the manufacturer's instructions from the phospho-Akt (Ser473) assay kit in whole cell lysate (MSD # K15100D-3) and the phosphoAkt assay kit (Thr308) in whole cell lysate (MSD # K151DYD-3) using provided therein buffers for lysis, blocking and washing.

Briefly, at the end of the treatment period, the medium was removed by aspiration and the adherent cells were lysed in 50 μl ice-cold lysis buffer. MSD plates were supplied as precoated with immobilized anti-phospho-Akt antibodies (Ser473 and Thr308). After blocking, lysates from tissue culture plates were added and the plates were washed. Then a solution containing a detectable antibody (anti-total Akt antibody conjugated to the

- 52 037871

Sulfo-tag MSD, which is an electrochemiluminescent compound). Signals were detected using a SECTOR Imager 6000 from MSD and corresponded to phospho-Akt titers.

The data was processed. Percent inhibition values were plotted against the log concentration of test compounds and the best fit sigmoidal log concentration-effect curve was calculated using non-linear regression analysis. From these concentration-response curves, IC50 values were calculated. Five concentrations were used to fit the curve.

Table In shows the resulting IC50 values (nM) (n. O. Means not determined).

Table B

Conn. No. IC ₅₀ pAkt_S473 (μM) IC ₅₀ pAkt_Thr308 (μM) one 0.04 0.03 2 0, 18 0.43 3 0.07 0.04 four -0, 14 0.15 five -0, 1 0, 13 6 0.05 0.04 7 0.48 0.39 eight n. about. 0.29 nine -0.48 -0.46 10 > 0.51 > 0.51 eleven > 0.51 > 0.51 12 0.31 0, 11 13 0, 17 0, 08 fourteen 0.32 0.22 fifteen 0, 12 0, 09 sixteen 0.41 0, 18 17 -0.23 0, 19

Examples of possible compositions.

Active ingredient (a. I.) Used throughout the description of these examples refers to a compound of formula (I), including any tautomer or stereisomeric form thereof, or an N-oxide, pharmaceutically acceptable addition salt or solvate thereof; in particular to any of the compounds given in the examples.

Typical examples of formulations for the composition of the present invention are as follows.

1. Tablets.

The active ingredient is 5-50 mg.

Dicalcium phosphate - 20 mg.

Lactose - 30 mg

Talc - 10 mg.

Magnesium stearate 5 mg

Potato starch - up to 200 mg.

2. Suspension.

An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of the active ingredient, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water to 1 ml.

3. Injection form.

A composition for parenteral administration was prepared by mixing 1.5% (w / v) active ingredient in 0.9% NaCl solution or 10% by volume propylene glycol solution in water.

4. Ointment.

The active ingredient is 5-1000 mg.

Stearyl alcohol - 3 g.

Lanolin - 5 g.

White Vaseline - 15 g.

Water - up to 100 g.

In this example, the active ingredient can be replaced with the same amount of any compounds

53 037871 in accordance with the present invention, in particular the same number of any exemplary compounds.

Claims (15)

CLAIM 1. Compound of formula (I) R ¹ its tautomer or stereoisomeric form, where R ¹ represents hydrogen, -C (= O) OH, -C (= O) NH ₂ , -NH2, ''' R ² represents R ³ is C1-4 alkyl; -CH (OH) -CH2-R ^q ; C1-4αalkyl substituted at the same carbon with one —OH and one Het ¹ ; or C _1-4 alkyl substituted with one substituent selected from the group consisting of fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, - (C = O) -OC _{1- 4} α-alkyl, -NH- (C = O) -C1-4αalkyl, -NH- (SO2) -C1-4αalkyl, -N (CH3) -C1-4αalkyl-SO2-CH3, -NH-C1-4alkyl-SO2-CH3, -N (CH3) -C1-4alkyl-OH, -O- (C = O) -CH (NH2) -C1-4alkyl-Ar, -C (= O) -Het ¹ and -NH-C (= O) -Het ¹ ; - (C = O) -NH-C1-4alkyl-OH, -O- (C = O) -CH (NH2) -C1-4alkyl, - -NH-C _1-4 alkyl-OH, Het ¹ , -O-C (= O) -C _1-4 alkyl-Het ¹ , R ^q is Het ¹ , fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, -NH- (C = O) -C _1-4 α-alkyl, -NH- (SO2) -C1-4alkyl, -N (CH3) -C1-4alkyl-SO2-CH3, -NH-C1-4alkyl-SO2-CH3, -N (CH3) -C1-4alkyl-OH, -O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl, -O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar, or —NH — C _1-4 alkyl — OH; Ar is phenyl optionally substituted with one hydroxy; R ^4a is hydrogen, C1-4 alkyl, Het ^a, or C1-4 alkyl substituted with one or more substituents each independently selected from the group consisting of —OH, —NR5R ⁶ and Het ^a ; R ^4b is hydrogen, halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents; or R ^4a and R ^4b are taken together to form, together with the phenyl ring to which they are attached, the structures of formula (a-1), (a-2), (a-3), (a-4) or (a-5 ): X is -NH-, -O-, -N (C _1-3 αalkyl) - or -N (hydroxy-C _1-3 alkyl) -; 54 037871 both R ⁷ are the same and are selected from the group consisting of hydrogen, fluoro and methyl; or both R ⁷ substituents are taken together to form, together with the common carbon atom to which they are attached, cyclopropyl, cyclobutyl or oxetanyl; both R ⁸ are the same and are selected from the group consisting of hydrogen and methyl; or both R ⁸ are taken together to form, together with the common carbon atom to which they are attached, cyclopropyl, cyclobutyl or oxetanyl; R ⁵ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with one —OH; R ⁶ is hydrogen, C _1-6 alkyl, or C _1-6 alkyl substituted with one —OH; Het ¹ is a 4-, 5-, or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, —NH2, C _1-4 alkyl, —S (= O) ₂ - C _1-6 alkyl, —C _1-4 alkyl-S (= O) ₂ —C _1-6 alkyl, hydroxyl, C _1-4 alkyloxy, fluoro, cyano, and C _1-4 alkyl substituted with one hydroxy; or two substituents on the same carbon atom of said 4-, 5 or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring A; wherein Ring A is cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5-, or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) _p and N; wherein said cyclobutyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclyl optionally substituted with one or two substituents are C _1-4 alkyl, one substituent represents a C _1-4 alkul, and one substituent, representing hydroxy, or one substituent representing hydroxy; each Het ^a independently represents a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) p and N; wherein said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C _1-4 alkyl, —S (= O) ₂ —C _1-6 alkyl , hydroxy, —C _1-4 alkyl-S (= O) ₂ —C _1-6 alkyl and C _1-4 alkyl substituted with one hydroxy; or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring B; wherein ring B is cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from O, S, S (= O) p and N; wherein said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl are optionally substituted with one or two C _1-4 alkyl substituents, one C _1-4 alkyl substituent and one substituent, representing hydroxy, or one substituent representing hydroxy; p is 1 or 2; or a pharmaceutically acceptable addition salt. 2. The connection according to claim 1, where R ³ is C1-4 alkyl; C1-4alkyl substituted on the same carbon with one —OH and one Het ¹ ; or C1-4 alkyl substituted with one substituent selected from the group consisting of fluoro, -OH, -NH2, -O- (C = O) -C _1-4 alkyl, - (C = O) -O-C _{1- 4} alkyl, -NH- (C = O) -C _1-4 alkyl, -NH- (SO ₂ ) -C _1-4 alkyl, -N (CH ₃ ) -C _1-4 alkyl-SO ₂ -CH ₃ , -NH-C _1-4 alkyl-SO ₂ -CH ₃ , -N (CH ₃ ) -C _1-4 alkyl-OH, - (C = O) -NH-C _1-4 alkyl-OH, -O (C = O) -CH (NH ₂ ) -C _1-4 alkyl, -O- (C = O) -CH (NH ₂ ) -C _1-4 alkyl-Ar, ^and , -NH-C _1-4 alkyl-OH, Het ¹ , -O-C (= O) -C _1-4 alkyl-Het ¹ , -C (= O) -Het1 and -NH-C (= O) - Het1; R ^4a is hydrogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more substituents, each independently selected from the group consisting of —OH and —NR ⁵ R ⁶ ; R ^4b is hydrogen, halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents; or R ^4a and R ^4b are taken together to form, together with the phenyl ring to which they are attached, the structures of formula (a-1), (a-2), (a-3), (a-4) or (a-5 ); both R ⁷ are hydrogen; both R ⁸ are hydrogen. 3. The connection according to claim 1, where R ¹ is hydrogen or —NH ₂ ; - 55 037871 R ² represents R ³ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and Het ¹ ; R ^4a is C _1-4 alkyl; R ^4b is halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents; or R ^4a and R ^4b are taken together to form, together with the phenyl ring to which they are attached, the structures of formula (a-2); X is —N (C _1-3 alkyl) - or —N (hydroxy-C _1-3 alkyl) -; both R ⁷ are hydrogen; both R ⁸ are hydrogen; Het ¹ is a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom, each independently selected from S (= O) _p and N; wherein said 4-, 5, or 6-membered saturated heterocyclyl is optionally substituted with one or two hydroxyl substituents; or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form, together with the common carbon atom to which they are attached, ring A; wherein Ring A is cyclobutyl optionally substituted with one hydroxy substituent; p equals 2. 4. A compound according to claim 1, wherein X is —N (C _1-3 alkyl) - or —N (hydroxy C _1-3 alkyl) -. 5. A compound according to claim 1, wherein R ³ is C _1-4 alkyl or C _1-4 alkyl substituted with one substituent selected from the group consisting of —OH and Het ¹ . 6. The connection according to claim 1, where R ^4a is hydrogen, C1-4 alkyl, Het ^a, or C1-4 alkyl substituted with one or more substituents, each independently selected from the group consisting of —OH, —NR5R ⁶ and Het ^a ; R ^4b is hydrogen, halogen, C _1-4 alkyl, or C _1-4 alkyl substituted with one or more halogen substituents. 7. The connection according to claim 6, where R ^4a is C _1-4 alkyl; R ^4b is C _1-4 alkyl substituted with one or more halogen substituents. 8. A compound according to claim 1, wherein both R ⁷ are hydrogen and both R ⁸ are hydrogen. 9. A compound according to claim 1, wherein R ² is · 10. A compound according to claim 1 wherein R ¹ is hydrogen. 11. A pharmaceutical composition having an inhibitory activity against phosphoinositide-3 kinases (PI3K) beta, containing a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1-10. 12. Use of a compound according to any one of claims 1-10 for the treatment or prevention of PI3Kδ-mediated diseases. 13. Use of a compound according to any one of claims 1-10 for the treatment or prevention of PI3Kδ-mediated diseases or conditions selected from cancer, autoimmune disorders, cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, allergies, pancreatitis, asthma, multiple organ failure, kidney disease, platelet aggregation, impaired sperm motility, transplant rejection, tissue rejection, and lung damage. 14. Use according to claim 13, wherein the disease or condition is cancer. 15. Use according to claim 14, wherein the disease or condition is prostate cancer.